| 1 | Am. J. Hum. Genet. 2002 Oct 71: 877-92 |
|---|---|
| PMID | 12145742 |
| Title | Neuregulin 1 and susceptibility to schizophrenia. |
| Abstract | The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 2 | Exp. Cell Res. 2003 Mar 284: 14-30 |
| PMID | 12648463 |
| Title | Neuregulins: functions, forms, and signaling strategies. |
| Abstract | The neuregulins (NRGs) are cell-cell signaling proteins that are ligands for receptor tyrosine kinases of the ErbB family. The neuregulin family of genes has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins, and they are considered in this review only briefly. The NRG1 proteins play essential roles in the nervous system, heart, and breast. There is also evidence for involvement of NRG signaling in the development and function of several other organ systems, and in human disease, including the pathogenesis of schizophrenia and breast cancer. There are many NRG1 isoforms, raising the question "Why so many neuregulins?" Study of mice with targeted mutations ("knockout mice") has demonstrated that isoforms differing in their N-terminal region or in their epidermal growth factor (EGF)-like domain differ in their in vivo functions. These differences in function might arise because of differences in expression pattern or might reflect differences in intrinsic biological characteristics. While differences in expression pattern certainly contribute to the observed differences in in vivo functions, there are also marked differences in intrinsic characteristics that may tailor isoforms for specific signaling requirements, a theme that will be emphasized in this review. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 3 | Pharmacopsychiatry 2003 Nov 36 Suppl 3: S195-202 |
| PMID | 14677079 |
| Title | Genetics of schizophrenia and affective disorders. |
| Abstract | The molecular-genetic basis of non-mendelian, genetically influenced disorders (complex disorders) is beginning to be uncovered. Recently, major progress in localization and detection of disposition genes of schizophrenia and bipolar disorder was achieved. We provide a comprehensive overview of recent results of linkage and association studies in schizophrenia and bipolar disorder. Several disposition genes for schizophrenia (DTNBP1, NRG1, G72) were identified, whereas evidence for specific disposition genes in bipolar disorder is more limited. Multiple limitations of current research strategies in the search of disposition genes of complex disorders have to be considered; alternative phenotype definitions, genome-wide association studies and parallel investigation of epigenetic misregulations might overcome these limitations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 4 | Mol. Psychiatry 2003 Jul 8: 706-9 |
| PMID | 12874607 |
| Title | Association study of neuregulin 1 gene with schizophrenia. |
| Abstract | A number of studies have indicated that 8p22-p12 is likely to harbor schizophrenia susceptibility loci. In this region, the candidate gene of interest, neuregulin 1 (NRG1), may play a role in the pathogenesis of schizophrenia. Then in the present study, we performed the linkage disequilibrium to determine the association between three genetic variants (SNPs: rs3924999, rs2954041, SNP8NRG221533) on NRG1 gene and schizophrenia in 246 Chinese Han schizophrenic family trios using PCR-based restriction fragment length polymorphism method and denaturing high-performance liquid chromatography. The transmission disequilibrium test analysis for each variant showed a significant difference between two transmitted alleles even after Bonferroni correction (rs3924999, P=0.007752; rs2954041, P=0.0009309; SNP8NRG221533, P=0.012606). The global chi(2) test for haplotype transmission also revealed a strong association (chi(2)=46.068, df=7, P&<0.000001). Our results suggest that the NRG1 gene may play a role in conferring susceptibility to the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 5 | Mol. Psychiatry 2003 Jul 8: 706-9 |
| PMID | 12874607 |
| Title | Association study of neuregulin 1 gene with schizophrenia. |
| Abstract | A number of studies have indicated that 8p22-p12 is likely to harbor schizophrenia susceptibility loci. In this region, the candidate gene of interest, neuregulin 1 (NRG1), may play a role in the pathogenesis of schizophrenia. Then in the present study, we performed the linkage disequilibrium to determine the association between three genetic variants (SNPs: rs3924999, rs2954041, SNP8NRG221533) on NRG1 gene and schizophrenia in 246 Chinese Han schizophrenic family trios using PCR-based restriction fragment length polymorphism method and denaturing high-performance liquid chromatography. The transmission disequilibrium test analysis for each variant showed a significant difference between two transmitted alleles even after Bonferroni correction (rs3924999, P=0.007752; rs2954041, P=0.0009309; SNP8NRG221533, P=0.012606). The global chi(2) test for haplotype transmission also revealed a strong association (chi(2)=46.068, df=7, P&<0.000001). Our results suggest that the NRG1 gene may play a role in conferring susceptibility to the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 6 | Lancet 2003 Feb 361: 417-9 |
| PMID | 12573388 |
| Title | Genes for schizophrenia? Recent findings and their pathophysiological implications. |
| Abstract | schizophrenia is highly heritable, but the genes have remained elusive. Identifying the genes is essential if the pathogenesis and pathophysiology of schizophrenia is finally to be understood, and to give the prospect of more effective treatment. H Stefansson and colleagues (Am J Hum Genet 2002; 71: 877-92) showed association of the neuregulin (NRG1) gene with schizophrenia. Other recent papers describe six additional susceptibility genes. Replications are already being reported for some of them. The genes are biologically plausible, and may have convergent effects on glutamatergic and other synapses. We review the evidence for each gene, the possible pathogenic mechanisms, and the implications of the findings. WHERE NEXT? Given earlier failures to replicate apparent breakthroughs, the results should be viewed with caution. Unequivocal replications remain the top priority. The respective contributions of each gene, epistatic effects, and functional interactions between the gene products, all need investigation. Confirmation that any of the genes is a true susceptibility gene for schizophrenia could trigger the same rapid therapeutic progress as has occurred recently in Alzheimer's disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 7 | Hum. Mol. Genet. 2003 Oct 12 Spec No 2: R125-33 |
| PMID | 12952866 |
| Title | Recent advances in the genetics of schizophrenia. |
| Abstract | The high heritability of schizophrenia has stimulated much work aimed at identifying susceptibility genes using positional genetics. As a result, several strong and well-established linkages have emerged. Three of the best-supported regions are 6p24-22, 1q21-22 and 13q32-34 where single studies have achieved genome-wide significance at P<0.05 and suggestive positive findings have also been reported in other samples. Other promising regions include 8p21-22, 6q21-25, 22q11-12, 5q21-q33, 10p15-p11 and 1q42. Recently, evidence implicating individual genes within some of the linked regions has been reported and more importantly replicated. Currently, the weight of evidence supports NRG1 and DTNBP1 as schizophrenia susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection. The evidence for COMT, RGS4 and G72 is promising but not yet persuasive. While it is essential that further replications are established, the respective contributions of each gene, relationships with aspects of the phenotype, the possibility of epistatic interactions between genes and functional interactions between the gene products will all need investigation. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research, and all the signs are that genetic research is poised to deliver crucial insights into the nature of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 8 | Am. J. Hum. Genet. 2003 Jan 72: 83-7 |
| PMID | 12478479 |
| Title | Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. |
| Abstract | Recently, we identified neuregulin 1 (NRG1) as a susceptibility gene for schizophrenia in the Icelandic population, by a combined linkage and association approach. Here, we report the first study evaluating the relevance of NRG1 to schizophrenia in a population outside Iceland. Markers representing a core at-risk haplotype found in Icelanders at the 5' end of the NRG1 gene were genotyped in 609 unrelated Scottish patients and 618 unrelated Scottish control individuals. This haplotype consisted of five SNP markers and two microsatellites, which all appear to be in strong linkage disequilibrium. For the Scottish patients and control subjects, haplotype frequencies were estimated by maximum likelihood, using the expectation-maximization algorithm. The frequency of the seven-marker haplotype among the Scottish patients was significantly greater than that among the control subjects (10.2% vs. 5.9%, P=.00031). The estimated risk ratio was 1.8, which is in keeping with our report of unrelated Icelandic patients (2.1). Three of the seven markers in the haplotype gave single-point P values ranging from .000064 to .0021 for the allele contributing to the at-risk haplotype. This direct replication of haplotype association in a second population further implicates NRG1 as a factor that contributes to the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 9 | Curr Psychiatry Rep 2004 Aug 6: 303-12 |
| PMID | 15260947 |
| Title | The genes for schizophrenia: finally a breakthrough? |
| Abstract | A number of susceptibility genes for schizophrenia have recently been identified. They have engendered excitement because replicate studies have attained greater consistency than in the past. In this review, we outline gene mapping methods, and briefly review their strengths and challenges. We also evaluate peer-reviewed genetic association studies that have implicated six selected genes: catechol-O-methyl transferase (COMT), neuregulin 1 (NRG1), dysbindin (DTNBP1), regulator of G-protein signaling 4 (RGS4), and G72 and D-amino-acid oxidase (DAAO). The available supporting evidence is variable. Though credible evidence is available for all of these genes, it is strongest for NRG1 and DTNBP1. Further studies, particularly exhaustive analyses of all polymorphisms at each locus, meta-analyses, and investigations of the likely function of risk alleles (variants) are desirable. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 10 | Neuroreport 2004 Nov 15: 2517-20 |
| PMID | 15538186 |
| Title | Neuregulin genotype and medication response in Finnish patients with schizophrenia. |
| Abstract | Neuregulin 1 is involved both in neurodevelopment and neurotransmitter mechanisms in the brain. There is evidence of an association between neuregulin 1 genotype and schizophrenia. We compared neuregulin 1 genotypes in patients with schizophrenia (n=94) and control subjects (n=395) of Finnish origin by using one SNP (SNP8NRG221533) as a genetic marker. We also analyzed NRG1 genotype with regard to age at onset and between responders and non-responders to conventional antipsychotics. The NRG1 genotype or allele frequencies showed similar distributions between patient and control groups. Age at onset was not associated with NRG1 genotype. The TT genotype was overrepresented in the non-responders group compared with the responders (p=0.013). Further studies are needed to ascertain the significance of neuregulin genotype in medication response to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 11 | Genes Brain Behav. 2004 Aug 3: 240-8 |
| PMID | 15248869 |
| Title | The contribution of three strong candidate schizophrenia susceptibility genes in demographically distinct populations. |
| Abstract | Here we characterize and compare the contribution of three recently identified strong candidate schizophrenia susceptibility genes; G72, neuregulin 1 (NRG1) and dystrobrevin-binding protein 1 (DTNBP1) in two independent datasets of patients with distinct genetic backgrounds. On the basis of corrected P-values from single- and multilocus transmission distortion tests our analysis provides no support for a contribution of G72, NRG1 or DTNBP1 in the tested samples. When transmission of individual haplotypes was considered, a picture more consistent with the original studies emerged, where transmission distortions in the same direction as the original samples and involving the same core haplotypes were observed for G72 and NRG1. Interestingly, whereas the NRG1 gene analysis was dominated by the presence of over-transmitted haplotypes, the G72 gene analysis was consistently dominated in both datasets by under-transmissions. Negative transmissions involved a core haplotype complementary to the originally detected over-transmitted haplotype, suggesting the presence of a protective variant within the G72 locus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 12 | Hippocampus 2004 -1 14: 337-44 |
| PMID | 15132433 |
| Title | Neuregulin1 downregulates postsynaptic GABAA receptors at the hippocampal inhibitory synapse. |
| Abstract | The growth factor neuregulin 1 (NRG1) has been proposed to contribute to the formation and maturation of neuromuscular and interneuronal synapses by upregulating the expression of specific neurotransmitter receptor subunits. In the present report, we show that, in the hippocampus, NRG1 is expressed in a pattern suggesting that it regulates synapse development in the CA1 region. However, in contrast to what has been shown in other synapses, NRG1 reduces the expression of gamma-aminobutyric acid (GABA)A receptors alpha subunits in hippocampal slices, and the mean amplitude of GABAergic miniature inhibitory postsynaptic currents (IPSCs) in hippocampal CA1 pyramidal neurons, without affecting IPSC kinetics or frequency. These effects of NRG1 occur without concomitant changes in glutamate receptors and other synaptic proteins. We propose that the role of NRG1 in the formation and maturation in the hippocampal inhibitory synapse is downregulation, rather than upregulation, of receptor subunit expression. These results suggest that NRG1 may contribute to the reduction in GABAergic synaptic activity in hippocampal CA1 pyramidal neurons that normally occurs during early postnatal development, and that alterations in NRG1 signaling in the hippocampus may contribute to schizophrenia and epilepsy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 13 | Nat. Neurosci. 2004 Jun 7: 575-80 |
| PMID | 15162166 |
| Title | Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia. |
| Abstract | schizophrenia is a devastating psychiatric disease that affects 0.5-1% of the world's adult population. The hypothesis that this disease is a developmental disorder of the nervous system with late onset of its characteristic symptoms has been gaining acceptance in past years. However, the anatomical, cellular and molecular bases of schizophrenia remain unclear. Numerous studies point to alterations in different aspects of brain development as possible causes of schizophrenia, including defects in neuronal migration, neurotransmitter receptor expression and myelination. Recently, the gene that encodes neuregulin-1 (NRG1) has been identified as a potential susceptibility gene for schizophrenia, and defects in the expression of erbB3, one of the NRG1 receptors, have been shown to occur in the prefrontal cortex of schizophrenic patients, suggesting that NRG1-erbB signaling is involved in the pathogenesis of schizophrenia. These findings open new approaches to defining the molecular and cellular basis of schizophrenia in more mechanistic terms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 14 | Nat. Neurosci. 2004 Jun 7: 575-80 |
| PMID | 15162166 |
| Title | Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia. |
| Abstract | schizophrenia is a devastating psychiatric disease that affects 0.5-1% of the world's adult population. The hypothesis that this disease is a developmental disorder of the nervous system with late onset of its characteristic symptoms has been gaining acceptance in past years. However, the anatomical, cellular and molecular bases of schizophrenia remain unclear. Numerous studies point to alterations in different aspects of brain development as possible causes of schizophrenia, including defects in neuronal migration, neurotransmitter receptor expression and myelination. Recently, the gene that encodes neuregulin-1 (NRG1) has been identified as a potential susceptibility gene for schizophrenia, and defects in the expression of erbB3, one of the NRG1 receptors, have been shown to occur in the prefrontal cortex of schizophrenic patients, suggesting that NRG1-erbB signaling is involved in the pathogenesis of schizophrenia. These findings open new approaches to defining the molecular and cellular basis of schizophrenia in more mechanistic terms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 15 | Ann. Med. 2004 -1 36: 62-71 |
| PMID | 15000348 |
| Title | Neuregulin 1 and schizophrenia. |
| Abstract | We discuss in this review the role of the neuregulin (NRG1) gene in schizophrenia. NRG1 contributes to the genetics of schizophrenia in both Icelandic and Scottish schizophrenia patients. NRG1 participates in glutamatergic signaling by regulating the N-methyl-D-aspartate (NMDA) receptor through the interaction of the NRG1 protein and its receptors. NRG1 plays a central role in neural development and is most likely involved in regulating synaptic plasticity, or how the brain responds or adapts to the environment. The discovery that defects in NRG1 signaling may be involved in some cases of schizophrenia, not only implicates NRG1, but suggests that its biological pathway, active both at developing and mature synapses, is worth inspecting further in a search for other schizophrenia genes possibly in epistasis with NRG1. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 16 | Mol. Psychiatry 2004 Feb 9: 208-13 |
| PMID | 14966480 |
| Title | Confirmation and refinement of an 'at-risk' haplotype for schizophrenia suggests the EST cluster, Hs.97362, as a potential susceptibility gene at the Neuregulin-1 locus. |
| Abstract | Two recent association studies have implicated the neuregulin-1 gene (NRG1) at chromosome 8p21-22 as a susceptibility gene for schizophrenia. Stefansson et al identified three 'at-risk' haplotypes (HapA, B and C) which spanned the NRG1 locus and shared a common core haplotype. Subsequently, they demonstrated evidence that the core haplotype was associated with schizophrenia in an independent Scottish sample. To confirm and refine this haplotype we investigated the NRG1 locus in an independent Irish case-control sample. We did not find the core haplotype to be associated in our sample. However, we identified a refined 2-marker haplotype (HapB(IRE)) that shared common alleles with one of the Icelandic 'at-risk' haplotypes and is in significant excess in the Irish cases (19.4%) vs controls (12.3%) (P=0.013). This refined 'at-risk' haplotype is also in significant excess in the Scottish case sample (17.0% vs 13.5%; P=0.036). Interestingly, this refined 'at-risk' haplotype is positioned close to an EST cluster of unknown function (Hs.97362) within intron 1 of NRG1. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 17 | Neurosci. Lett. 2004 Aug 366: 158-61 |
| PMID | 15276238 |
| Title | Case-control and family-based association studies between the neuregulin 1 (Arg38Gln) polymorphism and schizophrenia. |
| Abstract | Genetic variations in the neuregulin 1 (NRG1), a critical gene in neuronal development, have been reported to be associated with schizophrenia in several reports. Association has been reported between a non-synonymous NRG1 polymorphism (Arg38Gln) and schizophrenia in a Chinese family-based association study; however, this finding is not yet confirmed by other research findings analyzed using independent sample. To replicate this finding and assess the association between age at onset of schizophrenia and the NRG1 Arg38Gln polymorphism, we investigated the prevalence of this polymorphism in a Chinese population (228 schizophrenic disorder patients and 269 controls). We were unable, however, to demonstrate a significant association between the NRG1 Arg38Gln polymorphism and schizophrenia (P = 0.869 for genotype and P = 0.597 for allelic frequencies) or age at onset (P = 0.940). Our family-based association study (15 schizophrenic bios and 221 schizophrenic trios) demonstrated 38Gln was transmitted in excess by the parent to the affected offspring (P = 0.052). However, this result contrasts with a previous finding in Chinese that 38Arg was transmitted in excess by the parent to the affected offspring. On the basis of the contrast between the findings of other study and our family-based study and the negative findings of our case-control association study, we conclude that NRG1 Arg38Gln polymorphism is not likely to play a major role in the pathogenesis of schizophrenia in Chinese populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 18 | Neuroscience 2004 -1 127: 125-36 |
| PMID | 15219675 |
| Title | Neuregulin-1 (NRG-1) mRNA and protein in the adult human brain. |
| Abstract | Neuregulin-1 (NRG-1) plays important roles in the development and plasticity of the brain, and it has recently been identified as a susceptibility gene for schizophrenia. Though there are rodent data, little is known about its distribution in the human brain. The aim of this study was to ascertain the localization of NRG-1 and its mRNA in multiple regions of the normal adult human brain. We investigated NRG-1 mRNA in 11 subjects using in situ hybridization and northern analysis, and NRG-1 protein in six subjects using immunohistochemistry and Western blotting. NRG-1 mRNA was present as bands of approximately 2, 3 and 6 kb. It was clearly detected in the prefrontal cortex (middle laminae), hippocampal formation (except CA1), cerebellum, oculomotor nucleus, superior colliculus, red nucleus and substantia nigra pars compacta. At the cellular level, NRG1 mRNA was abundant in hippocampal and cortical pyramidal neurons and some interneurons, and in cerebellar Purkinje cells and Golgi cells. NRG-1 protein was detected as bands of approximately 140, 110, 95 and 60 kD. Immunohistochemistry revealed NRG-1 in many cell populations, consistent with the mRNA data, being prominent in pyramidal neurons, Purkinje cells, several brainstem nuclei, and white matter neurons. Moderate NRG-1 immunoreactivity was also observed in cerebellar and dentate gyrus granule cells, and some glia. Within neurons, NRG-1 staining was primarily somatodendritic; in the cell body staining was granular, with clustering close to the plasma and nuclear membranes. There was also labeling of some fiber tracts, and local areas of neuropil (e.g. in the dentate nucleus) suggestive of a pre-synaptic location of NRG-1. The data show a widespread expression of NRG-1 in the adult human brain, including, but not limited to, brain areas and cell populations implicated in schizophrenia. Using these normative data, future studies can ascertain whether the role of NRG-1 in the disease is mediated, or accompanied, via alterations in its expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 19 | Neurosci. Lett. 2004 Aug 366: 158-61 |
| PMID | 15276238 |
| Title | Case-control and family-based association studies between the neuregulin 1 (Arg38Gln) polymorphism and schizophrenia. |
| Abstract | Genetic variations in the neuregulin 1 (NRG1), a critical gene in neuronal development, have been reported to be associated with schizophrenia in several reports. Association has been reported between a non-synonymous NRG1 polymorphism (Arg38Gln) and schizophrenia in a Chinese family-based association study; however, this finding is not yet confirmed by other research findings analyzed using independent sample. To replicate this finding and assess the association between age at onset of schizophrenia and the NRG1 Arg38Gln polymorphism, we investigated the prevalence of this polymorphism in a Chinese population (228 schizophrenic disorder patients and 269 controls). We were unable, however, to demonstrate a significant association between the NRG1 Arg38Gln polymorphism and schizophrenia (P = 0.869 for genotype and P = 0.597 for allelic frequencies) or age at onset (P = 0.940). Our family-based association study (15 schizophrenic bios and 221 schizophrenic trios) demonstrated 38Gln was transmitted in excess by the parent to the affected offspring (P = 0.052). However, this result contrasts with a previous finding in Chinese that 38Arg was transmitted in excess by the parent to the affected offspring. On the basis of the contrast between the findings of other study and our family-based study and the negative findings of our case-control association study, we conclude that NRG1 Arg38Gln polymorphism is not likely to play a major role in the pathogenesis of schizophrenia in Chinese populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 20 | Mol. Psychiatry 2004 Aug 9: 777-83; image 729 |
| PMID | 15197397 |
| Title | No evidence for linkage or association of neuregulin-1 (NRG1) with disease in the Irish study of high-density schizophrenia families (ISHDSF). |
| Abstract | The neuregulin-1 gene (NRG1) at chromosome 8p21-22 has been implicated as a schizophrenia susceptibility gene in Icelandic, Scottish, Irish and mixed UK populations. The shared ancestry between these populations led us to investigate the NRG1 polymorphisms and appropriate marker haplotypes for linkage and/or association to schizophrenia in the Irish study of high-density schizophrenia families (ISHDSF). Neither single-point nor multi-point linkage analysis of NRG1 markers gave evidence for linkage independent of our pre-existing findings telomeric on 8p. Analysis of linkage disequilibrium (LD) across the 252 kb interval encompassing the 7 marker core Icelandic/Scottish NRG1 haplotype revealed two separate regions of modest LD, comprising markers SNP8NRG255133, SNP8NRG249130 and SNP8NRG243177 (telomeric) and microsatellites 478B14-428, 420M9-1395, D8S1810 and 420M9-116I12 (centromeric). From single marker analysis by TRANSMIT and FBAT we found no evidence for association with schizophrenia for any marker. Haplotype analysis for the three SNPs in LD region 1 and, separately, the four microsatellites in LD region 2 (analyzed in overlapping 2-marker windows), showed no evidence for overtransmission of specific haplotypes to affected individuals. We therefore conclude that if NRG1 does contain susceptibility alleles for schizophrenia, they impact quite weakly on risk in the ISHDSF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 21 | Mol. Psychiatry 2004 Jul 9: 698-704 |
| PMID | 15007393 |
| Title | Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype. |
| Abstract | To determine if neuregulin 1 (NRG1) is associated with schizophrenia in Asian populations, we investigated a Han Chinese population using both a family trio design and a case-control design. A total of 25 microsatellite markers and single nucleotide polymorphisms (SNPs) were genotyped spanning the 1.1 Mb NRG1 gene including markers of a seven-marker haplotype at the 5' end of the gene found to be in excess in Icelandic and Scottish schizophrenia patients. The alleles of the individual markers forming the seven marker at-risk haplotype are not likely to be causative as they are not in excess in patients in the Chinese population studied here. However using unrelated patients, we find a novel haplotype (HAP(China 1)), immediately upstream of the Icelandic haplotype, in excess in patients (11.9% in patients vs 4.2% in controls; P=0.0000065, risk ratio (rr) 3.1), which was not significant when parental controls were used. Another haplotype (HAP(China 2)) overlapping the Icelandic risk haplotype was found in excess in the Chinese (8.5% of patients vs 4.0% of unrelated controls; P=0.003, rr 2.2) and was also significant using parental controls only (P=0.0047, rr 2.1). A four-marker haplotype at the 3' end of the NRG1 gene, HAP(China 3), was found at a frequency of 23.8% in patients and 13.7% in nontransmitted parental haplotypes (P=0.000042, rr=2.0) but was not significant in the case-control comparison. We conclude that different haplotypes within the boundaries of the NRG1 gene may be associated with schizophrenia in the Han Chinese. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 22 | Mol. Psychiatry 2004 Jan 9: 14-27 |
| PMID | 14581932 |
| Title | The molecular genetics of schizophrenia: new findings promise new insights. |
| Abstract | The high heritability of schizophrenia has stimulated much work aimed at identifying susceptibility genes using positional genetics. However, difficulties in obtaining clear replicated linkages have led to the scepticism that such approaches would ever be successful. Fortunately, there are now signs of real progress. Several strong and well-established linkages have emerged. Three of the best-supported regions are 6p24-22, 1q21-22 and 13q32-34. In these cases, single studies achieved genome-wide significance at P<0.05 and suggestive positive findings have also been reported in other samples. The other promising regions include 8p21-22, 6q21-25, 22q11-12, 5q21-q33, 10p15-p11 and 1q42. The study of chromosomal abnormalities in schizophrenia has also added to the evidence for susceptibility loci at 22q11 and 1q42. Recently, evidence implicating individual genes within some of the linked regions has been reported and more importantly replicated. The weight of evidence now favours NRG1 and DTNBP1 as susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection. The evidence for catechol-O-methyl transferase, RGS4 and G72 is promising but not yet persuasive. While further replications remain the top priority, the respective contributions of each gene, relationships with aspects of the phenotype, the possibility of epistatic interactions between genes and functional interactions between the gene products will all need investigation. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research, and all the signs are that it is now poised to deliver crucial insights into the nature of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 23 | J. Med. Genet. 2005 Mar 42: 193-204 |
| PMID | 15744031 |
| Title | The genetics of schizophrenia and bipolar disorder: dissecting psychosis. |
| Abstract | Much work has been done to identify susceptibility genes in schizophrenia and bipolar disorder. Several well established linkages have emerged in schizophrenia. Strongly supported regions are 6p24-22, 1q21-22, and 13q32-34, while other promising regions include 8p21-22, 6q16-25, 22q11-12, 5q21-q33, 10p15-p11, and 1q42. Genomic regions of interest in bipolar disorder include 6q16-q22, 12q23-q24, and regions of 9p22-p21, 10q21-q22, 14q24-q32, 13q32-q34, 22q11-q22, and chromosome 18. Recently, specific genes or loci have been implicated in both disorders and, crucially, replicated. Current evidence supports NRG1, DTNBP1, DISC1, DAOA(G72), DAO, and RGS4 as schizophrenia susceptibility loci. For bipolar disorder the strongest evidence supports DAOA(G72) and BDNF. Increasing evidence suggests an overlap in genetic susceptibility across the traditional classification systems that dichotomised psychotic disorders into schizophrenia or bipolar disorder, most notably with association findings at DAOA(G72), DISC1, and NRG1. Future identification of psychosis susceptibility genes will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 24 | Trends Genet. 2005 Sep 21: 518-25 |
| PMID | 16009449 |
| Title | Schizophrenia: genes at last? |
| Abstract | Genetic epidemiological studies suggest that individual variation in susceptibility to schizophrenia is largely genetic, reflecting alleles of moderate to small effect in multiple genes. Molecular genetic studies have identified several potential regions of linkage and two associated chromosomal abnormalities, and evidence is accumulating in favour of several positional candidate genes. Currently, the positional candidate genes for which we consider the evidence to be strong are those encoding dysbindin (DTNBP1) and neuregulin 1 (NRG1). For other genes, disrupted in schizophrenia 1 (DISC1), D-amino-acid oxidase (DAO), D-amino-acid oxidase activator (DAOA, formerly known as G72) and regulator of G-protein signalling 4 (RGS4), the data are promising but not yet compelling. The identification of these, and other susceptibility genes, will open up new avenues for research aimed at understanding the pathogenesis of schizophrenia, and will catalyse a re-appraisal of the classification of psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 25 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Apr 134B: 79-83 |
| PMID | 15704228 |
| Title | Linkage evidence of schizophrenia to loci near neuregulin 1 gene on chromosome 8p21 in Taiwanese families. |
| Abstract | Positive linkage of schizophrenia to chromosome 8p22-21 loci had been reported in the Caucasian samples. This study was designed to replicate this finding by using eleven microsatellite markers on chromosome 8p22-21 in 52 Taiwanese schizophrenic families with at least two affected siblings. Two phenotype models (narrow: DSM-IV schizophrenia only; and broad: including schizophrenia, schizoaffective, and other non-affective psychotic disorders) were used to define the disease phenotype. Maximum non-parametric linkage scores (NPL score) of 2.45 (P = 0.008) and 1.89 (P = 0.02) were obtained for the marker D8S1222 under the broad and narrow models, respectively. Positive linkage was found across about a 4-cM region. The marker D8S1222 was about 400 kbp distal to the exon 1 of glial growth factor 2 (GGF2), an isoform of Neuregulin 1 gene (NRG1), which has been highly suggested to be a candidate gene for schizophrenia. The results provide suggestive linkage evidence of schizophrenia to loci near NRG1 on chromosome 8p21 in an ethnically distinct Taiwanese sample. Further exploration of the candidate gene and nearby chromosome regions is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 26 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Apr 134B: 79-83 |
| PMID | 15704228 |
| Title | Linkage evidence of schizophrenia to loci near neuregulin 1 gene on chromosome 8p21 in Taiwanese families. |
| Abstract | Positive linkage of schizophrenia to chromosome 8p22-21 loci had been reported in the Caucasian samples. This study was designed to replicate this finding by using eleven microsatellite markers on chromosome 8p22-21 in 52 Taiwanese schizophrenic families with at least two affected siblings. Two phenotype models (narrow: DSM-IV schizophrenia only; and broad: including schizophrenia, schizoaffective, and other non-affective psychotic disorders) were used to define the disease phenotype. Maximum non-parametric linkage scores (NPL score) of 2.45 (P = 0.008) and 1.89 (P = 0.02) were obtained for the marker D8S1222 under the broad and narrow models, respectively. Positive linkage was found across about a 4-cM region. The marker D8S1222 was about 400 kbp distal to the exon 1 of glial growth factor 2 (GGF2), an isoform of Neuregulin 1 gene (NRG1), which has been highly suggested to be a candidate gene for schizophrenia. The results provide suggestive linkage evidence of schizophrenia to loci near NRG1 on chromosome 8p21 in an ethnically distinct Taiwanese sample. Further exploration of the candidate gene and nearby chromosome regions is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 27 | Psychol Med 2005 Nov 35: 1599-610 |
| PMID | 16219118 |
| Title | Neuregulin 1 (NRG1 ) and schizophrenia: analysis of a US family sample and the evidence in the balance. |
| Abstract | Individual genome-wide linkage scans and meta-analyses support that one or more susceptibility genes for schizophrenia are located in chromosome 8p. A gene from this region, neuregulin 1 (NRG1 ), known to be involved with glutamatergic function, has been found to be associated in some studied samples. We have examined a new combined schizophrenia sample with 136 schizophrenia families largely of European ancestry (EA) and 646 subjects with DNA. We genotyped 14 single nucleotide polymorphisms (SNPs) in NRG1 including those reported to comprise schizophrenia-associated haplotypes in Icelandic, Scottish, Irish, and Chinese Han populations. We found no evidence of association at a single-marker or a haplotypic level. We review methodological aspects of previous studies to enable us to put our findings into context. Our failure to find an association between NRG1 and schizophrenia might reflect different linkage disequilibrium (LD) patterns found in different populations, disease allelic heterogeneity, clinical heterogeneity of schizophrenia, or inadequate statistical power deriving from moderate sample size. NRG1, if a true gene for schizophrenia, accounts for a small fraction of the disease in most populations. The confirmation of NRG1 as a schizophrenia susceptibility gene will require studies with a comprehensive set of markers and in larger samples. The possibility remains that reports of NRG1 association might reflect false positives. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 28 | Psychol Med 2005 Nov 35: 1589-98 |
| PMID | 16219117 |
| Title | Neuregulin 1 gene and variations in perceptual aberration of schizotypal personality in adolescents. |
| Abstract | We test the hypothesis that the neuregulin 1 (NRG1 ) gene at chromosome 8p22-p12, which has been implicated as a susceptibility gene to schizophrenia, is associated with variations in schizotypal personality in non-clinical populations. A randomly selected sample of 905 adolescents were assessed for their personality features using the Perceptual Aberration Scale (PAS) and the schizotypal Personality Questionnaire (SPQ) and genotyped for three single nucleotide polymorphisms (SNP8NRG221533, rs3924999, and rs2954041) at the NRG1 gene. Relations between the three genetic variants and continuous schizotypal personality scores were evaluated using ANOVA for single-locus analyses and haplotype trend regression test for multi-locus analyses. Single locus analysis showed that the A allele of rs3924999, a functional polymorphism in exon 2, had the largest effect size and exhibited a prominent allele-dose trend effect for the PAS score. Haplotype analyses using the haplotype trend regression test indicated that the A allele of rs3924999 was mainly responsible for the association with the PAS but not with the SPQ or its three factors, and the magnitude of significance was not strengthened by the combination of this allele with adjacent locus. Our study provides the first evidence for the association of NRG1 with schizotypal personality and indicates a possible role of NRG1 in the genetic etiology of schizophrenia through perceptual aberrations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 29 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Nov 139B: 28-32 |
| PMID | 16082692 |
| Title | Neuregulin-1 polymorphism in late onset Alzheimer's disease families with psychoses. |
| Abstract | Probands with late onset Alzheimer's disease (LOAD) exhibit positive symptoms of psychosis, 30-60% of the time. Positive symptoms of psychosis have been shown to appear prior to the onset of dementia to be accompanied by greater cognitive deficits, and to predict a more rapid decline. A study of the distribution of AD with psychosis (ADP) in families from the NIMH Alzheimer's Disease Genetic Initiative sample indicates that the trait is heritable, and linkage studies of multiplex ADP families have found suggestive peaks on 2p, 6q, 8p, and 21q. A genome scan of idiopathic psychosis, schizophrenia, in the Icelandic population identified a risk haplotype within the 5' region of neuregulin-1 (NRG1) on 8p12. Associations with NRG1 SNPs have also been found in other schizophrenia populations from Scotland, Ireland, and China. Here, we report results demonstrating a significant linkage peak for ADP on 8p12 in the NIMH AD dataset, encompassing the NRG1 region. We also demonstrate that there is a significant association with a NRG1 SNP (single nucleotide polymorphism), rs392499, with ADP, chi2 = 7.0, P = 0.008. This same SNP is part of a 3-SNP haplotype preferentially transmitted to individuals with this phenotype. Our results suggest that NRG1 plays a role in increasing the genetic risk to positive symptoms of psychosis in a proportion of LOAD families. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 30 | Schizophr Bull 2005 Jul 31: 613-7 |
| PMID | 16081509 |
| Title | Association between the neuregulin 1 gene and schizophrenia: a systematic review. |
| Abstract | Chromosome 8p22-p11 has been identified as a locus for schizophrenia in several genome-wide scans, which has been confirmed by meta-analysis of published linkage data. It appears to be 1 of the most robust linkage findings in psychosis. Several attempts have been made to identify the underlying genetic variation that gives rise to this linkage peak, including systematic fine mapping using extended Icelandic pedigrees that have identified an associated haplotype (HAP(ICE)) in the gene neuregulin 1, also known as heuregulin, glial growth factor, NDF43, and ARIA. Neuregulin 1 (NRG1) is a plausible susceptibility gene because of its involvement in neurodevelopment, regulation of glutamate and other neurotransmitter receptor expression, and synaptic plasticity. Encouragingly, this finding was quickly and directly replicated in a Scottish case-control sample by the same investigators with the same approximately 300 kb associated haplotype. Although in Caucasian populations subsequent attempts at replication of this finding have been difficult to interpret, and no individual functional or causative genetic variants have yet been identified, a summary of HAP(ICE) association results in about 4,500 subjects is consistent with a small (odds ratio approximately 1.5) but significant effect of this haplotype on schizophrenia risk. In Chinese Han populations, where HAP(ICE) is not found, there is good evidence from several studies of association with other markers in the same region. Overall, there is convincing but not yet compelling evidence for a role for NRG1 in susceptibility to schizophrenia. Other genes from this region have also been implicated in schizophrenia, not by systematic mapping but by positional candidate gene analysis; these include MSTP131, frizzled-3, and the calcineurin A gamma subunit gene. Not only are these alternative explanations for the linkage seen between chromosome 8p and schizophrenia, but it is equally possible that there is more than 1 susceptibility gene at this locus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 31 | Arch. Gen. Psychiatry 2005 Jun 62: 642-8 |
| PMID | 15939841 |
| Title | Operation of the schizophrenia susceptibility gene, neuregulin 1, across traditional diagnostic boundaries to increase risk for bipolar disorder. |
| Abstract | Family and twin data suggest that, in addition to susceptibility genes specific for bipolar disorder or schizophrenia, genes exist that contribute to susceptibility across the traditional kraepelinian divide. Several studies have provided evidence that variation at the neuregulin 1 (NRG1) gene on chromosome 8p12 influences susceptibility to schizophrenia. The most consistent finding has been that one particular haplotype (the "core" haplotype) is overrepresented in cases compared with control subjects. To investigate the possible role of NRG1 in bipolar disorder. Genetic case-control association analysis. Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services. Five hundred twenty-nine patients with DSM-IV bipolar I disorder and 1011 controls from the United Kingdom (100% white). We genotyped the markers constituting the NRG1 core haplotype in cases and controls and reanalyzed our existing data from 573 DSM-IV schizophrenia cases with this larger set of controls. We found a significant difference in haplotype distribution between bipolar cases and controls globally (P = .003) and specifically for the core haplotype. Frequencies were 10.2% for bipolar cases and 7.8% for controls (effect size, as measured by odds ratio [OR], 1.37; 95% confidence interval [CI], 1.03-1.80; P = .04). The effect size in our bipolar sample was similar to that in our schizophrenia sample (OR, 1.22; 95% CI, 0.92-1.61). In the bipolar cases with predominantly mood-incongruent psychotic features (n = 193), the effect was greater (OR, 1.71; 95% CI, 1.29-2.59; P = .009), as was the case in the subset of schizophrenia cases (n = 27) who had experienced mania (OR, 1.64; 95% CI, 0.54-5.01). Our findings suggest that neuregulin 1 plays a role in influencing susceptibility to bipolar disorder and schizophrenia and that it may exert a specific effect in the subset of functional psychosis that has manic and mood-incongruent psychotic features. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 32 | Mol. Psychiatry 2005 Apr 10: 366-74, 328 |
| PMID | 15545978 |
| Title | Support for involvement of neuregulin 1 in schizophrenia pathophysiology. |
| Abstract | schizophrenia is a common, multigenic psychiatric disorder. Linkage studies, including a recent meta-analysis of genome scans, have repeatedly implicated chromosome 8p12-p23.1 in schizophrenia susceptibility. More recently, significant association with a candidate gene on 8p12, neuregulin 1 (NRG1), has been reported in several European and Chinese samples. We investigated NRG1 for association in schizophrenia patients of Portuguese descent to determine whether this gene is a risk factor in this population. We tested NRG1 markers and haplotypes for association in 111 parent-proband trios, 321 unrelated cases, and 242 control individuals. Associations were found with a haplotype that overlaps the risk haplotype originally reported in the Icelandic population ("Hap(ICE)"), and two haplotypes located in the 3' end of NRG1 (all P<0.05). However, association was not detected with Hap(ICE) itself. Comparison of NRG1 transcript expression in peripheral leukocytes from schizophrenia patients and unaffected siblings identified 3.8-fold higher levels of the SMDF variant in patients (P=0.039). Significant positive correlations (P<0.001) were found between SMDF and HRG-beta 2 expression and between HRG-gamma and ndf43 expression, suggesting common transcriptional regulation of NRG1 variants. In summary, our results suggest that haplotypes across NRG1 and multiple NRG1 variants are involved in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 33 | Psychol Med 2005 Nov 35: 1589-98 |
| PMID | 16219117 |
| Title | Neuregulin 1 gene and variations in perceptual aberration of schizotypal personality in adolescents. |
| Abstract | We test the hypothesis that the neuregulin 1 (NRG1 ) gene at chromosome 8p22-p12, which has been implicated as a susceptibility gene to schizophrenia, is associated with variations in schizotypal personality in non-clinical populations. A randomly selected sample of 905 adolescents were assessed for their personality features using the Perceptual Aberration Scale (PAS) and the schizotypal Personality Questionnaire (SPQ) and genotyped for three single nucleotide polymorphisms (SNP8NRG221533, rs3924999, and rs2954041) at the NRG1 gene. Relations between the three genetic variants and continuous schizotypal personality scores were evaluated using ANOVA for single-locus analyses and haplotype trend regression test for multi-locus analyses. Single locus analysis showed that the A allele of rs3924999, a functional polymorphism in exon 2, had the largest effect size and exhibited a prominent allele-dose trend effect for the PAS score. Haplotype analyses using the haplotype trend regression test indicated that the A allele of rs3924999 was mainly responsible for the association with the PAS but not with the SPQ or its three factors, and the magnitude of significance was not strengthened by the combination of this allele with adjacent locus. Our study provides the first evidence for the association of NRG1 with schizotypal personality and indicates a possible role of NRG1 in the genetic etiology of schizophrenia through perceptual aberrations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 34 | Am J Psychiatry 2006 May 163: 940-1; author reply 941-2 |
| PMID | 16648345 |
| Title | Are high-risk haplotypes in DTNBP1 and NRG1 resistance genes for schizophrenia? |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 35 | Eur. J. Hum. Genet. 2006 Jun 14: 669-80 |
| PMID | 16721403 |
| Title | Molecular genetic studies of schizophrenia. |
| Abstract | The study of schizophrenia genetics has confirmed the importance of genes in etiology, but has not so far identified the relationship between observed genetic risks and specific DNA variants, protein alterations or biological processes. In spite of many limitations, numerous regions of the human genome give consistent, although by no means unanimous, support for linkage, which is unlikely to occur by chance. Two recent shifts have been evident in the field. First, a series of studies combining linkage and association analyses in the same family sets have identified promising candidate genes (DTNBP1, NRG1, G72/G30, TRAR4). Although a consensus definition of replication for genetic association in a complex trait remains difficult to achieve, the evidence for two of these (dystrobrevin binding protein 1 (DTNBP1), NRG1) is strong. Second, a series of studies combining association with functional investigation of changes in the associated gene in schizophrenia have also identified several candidate genes (COMT, RGS4, PPP3CC, ZDHHC8, AKT1). Somewhat surprisingly, the loci implicated by these studies have proven less robust in replication, although the number of replication studies remains small in several cases. Assessment of the combined evidence for the DTNBP1 gene gives some insight into the nature of the problems remaining to be solved. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 36 | Dialogues Clin Neurosci 2006 -1 8: 79-84 |
| PMID | 16640117 |
| Title | Clinical impact of recently detected susceptibility genes for schizophrenia. |
| Abstract | After years of frustration, the search for genes impacting on schizophrenia is now undergoing some exciting developments. Several proposals of susceptibility genes have been able to be supported by replications. Thus, there are now at least three very strong candidates: the gene for dysbindin (DTNBP1), the gene for neuregulin-1 (NRG1), and a less well-understood gene locus, G72/G30, which are likely to influence manifestations of schizophrenia. Other "hot" candidates such as the disrupted-in-schizophrenia 1 gene (DISC1) and the gene coding for protein kinase B (AKT1) might also prove to be susceptibility genes in the next future. The clinical implications of these findings are not yet fully visible. However, some first insights are possible: most of the genetic findings lack diagnostic specificity, and are also reproduced in bipolar disorder. Strong associations are also obtained on a symptomatic level, not only on a diagnostic level. The pathophysiological role of these hot candidate genes is currently under intensive study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 37 | Curr Opin Psychiatry 2006 Mar 19: 158-64 |
| PMID | 16612196 |
| Title | An update on the genetics of schizophrenia. |
| Abstract | This paper reviews recent molecular genetic studies of schizophrenia and evaluates claims implicating specific genes as susceptibility loci. Molecular genetic studies have identified several potential regions of linkage and two associated chromosomal abnormalities, and the evidence is accumulating in favour of several positional candidate genes. Currently, the strongest evidence for putative schizophrenia susceptibility loci relates to the genes encoding dysbindin (DTNBP1) and neuregulin (NRG1). For other genes, disrupted in schizophrenia (DISC1), D-amino acid oxidase activator (DAOA), regulator of G-protein signalling 4 (RGS4) and V-AKT murine thymoma viral oncogene homolog 1 (AKT1) the data are promising but not yet compelling. In the most convincing cases, the risk haplotypes appear to be associated with small effect sizes and do not fully explain the linkage findings that prompted each study. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research. Despite the accumulation of significant genetic data, however, the susceptibility variants have yet to be identified and detailed follow-up studies are now required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 38 | Nat. Med. 2006 Jul 12: 824-8 |
| PMID | 16767099 |
| Title | Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. |
| Abstract | Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia. Among NRG1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in the modulation of N-methyl-D-aspartate (NMDA) receptor signaling. Here, using a new postmortem tissue-stimulation approach, we show a marked increase in NRG1-induced activation of erbB4 in the prefrontal cortex in schizophrenia. Levels of NRG1 and erbB4, however, did not differ between schizophrenia and control groups. To evaluate possible causes for this hyperactivation of erbB4 signaling, we examined the association of erbB4 with PSD-95 (postsynaptic density protein of 95 kDa), as this association has been shown to facilitate activation of erbB4. schizophrenia subjects showed substantial increases in erbB4-PSD-95 interactions. We found that NRG1 stimulation suppresses NMDA receptor activation in the human prefrontal cortex, as previously reported in the rodent cortex. NRG1-induced suppression of NMDA receptor activation was more pronounced in schizophrenia subjects than in controls, consistent with enhanced NRG1-erbB4 signaling seen in this illness. Therefore, these findings suggest that enhanced NRG1 signaling may contribute to NMDA hypofunction in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 39 | Nat. Neurosci. 2006 Dec 9: 1477-8 |
| PMID | 17072305 |
| Title | A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms. |
| Abstract | NRG1, encoding neuregulin 1, is a susceptibility gene for schizophrenia, but no functional mutation causally related to the disorder has yet been identified. Here we investigate the effects of a variant in the human NRG1 promoter region in subjects at high risk of schizophrenia. We show that this variant is associated with (i) decreased activation of frontal and temporal lobe regions, (ii) increased development of psychotic symptoms and (iii) decreased premorbid IQ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 40 | Proc. Natl. Acad. Sci. U.S.A. 2006 Apr 103: 6747-52 |
| PMID | 16618933 |
| Title | Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5' SNPs associated with the disease. |
| Abstract | Genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated SNPs are noncoding, and their functional implications remain unknown. We hypothesized that differential expression of the NRG1 gene explains its association to the disease. We examined four of the disease-associated SNPs that make up the original risk haplotype in the 5' upstream region of the gene for their effects on mRNA abundance of NRG1 types I-IV in human postmortem hippocampus. Diagnostic comparisons revealed a 34% increase in type I mRNA in schizophrenia and an interaction of diagnosis and genotype (SNP8NRG221132) on this transcript. Of potentially greater interest, a single SNP within the risk haplotype (SNP8NRG243177) and a 22-kb block of this core haplotype are associated with mRNA expression for the novel type IV isoform in patients and controls. Bioinformatic promoter analyses indicate that both SNPs lead to a gain/loss of putative binding sites for three transcription factors, serum response factor, myelin transcription factor-1, and High Mobility Group Box Protein-1. These data implicate variation in isoform expression as a molecular mechanism for the genetic association of NRG1 with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 41 | Biol. Psychiatry 2006 Jul 60: 163-76 |
| PMID | 16616896 |
| Title | Critical appraisal of DNA microarrays in psychiatric genomics. |
| Abstract | Transcriptome profiling using DNA microarrays are data-driven approaches with the potential to uncover unanticipated relationships between gene expression alterations and psychiatric disorders. Studies to date have yielded both convergent and divergent findings. Differences may be explained, at least in part, by the use of a variety of microarray platforms and analytical approaches. Consistent findings across studies suggest, however, that important relationships may exist between altered gene expression and genetic susceptibility to psychiatric disorders. For example, GAD67, RGS4, DTNBP1, NRG1, and GABRAB2 show expression alterations in the postmortem brain of subjects with schizophrenia, and these genes have been also implicated as putative, heritable schizophrenia susceptibility genes. Thus, we propose that for some genes, altered expression in the postmortem human brain may have a dual origin: polymorphisms in the candidate genes themselves or upstream genetic-environmental factors that converge to alter their expression level. We hypothesize that certain gene products, which function as "molecular hubs," commonly show altered expression in psychiatric disorders and confer genetic susceptibility for one or more diseases. Microarray gene expression studies are ideally suited to reveal these putative disease-associated molecular hubs and to identify promising candidates for genetic association studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 42 | Mol. Psychiatry 2006 Jun 11: 539-46 |
| PMID | 16520822 |
| Title | Association of the NRG1 gene and schizophrenia: a meta-analysis. |
| Abstract | We investigated the association of the NRG1 gene and schizophrenia using meta-analytic techniques, combining all published data while restricting our analysis to studies investigating the most commonly reported single marker (SNP8NRG221533). We also investigated whether ancestry (European vs East Asian) and study design (family-based vs case-control) moderated any association. We found no evidence for an association of SNP8NRG221533 with schizophrenia, and significant between-study heterogeneity, which persisted when family-based studies were combined separately. However, when haplotype-based P-values were combined, there was evidence in support of an association of NRG1 with schizophrenia, and no evidence of between-study heterogeneity. Our meta-analysis provides support for the association of NRG1 with schizophrenia, but indicates that firmly establishing the role of NRG1 gene in schizophrenia by genetic association requires much larger sample sizes than have hitherto been reported. Association analyses and replications should take place at the level of the gene, rather than at the level of SNP, haplotype, or functional variant. Meta-analysis would then be carried out on the basis of the combination of P-values. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 43 | Biol. Psychiatry 2006 Jul 60: 132-40 |
| PMID | 16442083 |
| Title | Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. |
| Abstract | Neuregulin 1 (NRG1) is a leading schizophrenia susceptibility gene. The NRG1 locus on chromosome 8p shows linkage to the disorder, and genetic association has been found between schizophrenia and various non-coding polymorphisms and haplotypes, especially at the 5' end of the NRG1 gene, in many but not all case-control and family studies. NRG1 is a pleiotropic growth factor, important in nervous system development and functioning; roles include the modulation of neuronal migration, synaptogenesis, gliogenesis, neuron-glia communication, myelination, and neurotransmission. Understanding the neurobiology of NRG1 and its involvement in schizophrenia is challenged by the complexity of the gene, which gives rise to multiple functionally distinct isoforms, including six "types" of NRG1 defined by 5' exon usage. Type IV and type I NRG1 may be particularly relevant to schizophrenia, with initial data showing altered expression of these isoforms in the disorder or in association with NRG1 risk alleles. We review the structure and functions of NRG1, consider the evidence for and against it being a schizophrenia susceptibility gene, and discuss mechanisms that might underlie the contribution of NRG1 to disease pathophysiology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 44 | Brain Res Rev 2006 Aug 51: 161-75 |
| PMID | 16412517 |
| Title | Neuregulins: versatile growth and differentiation factors in nervous system development and human disease. |
| Abstract | The neuregulins are a family of growth and differentiation factors with a wide range of functions in the nervous system. The power and diversity of the neuregulin signaling system comes in part from a large number of alternatively-spliced forms of the NRG1 gene that can produce both soluble and membrane-bound forms. The soluble forms of neuregulin are unique from other factors in that they have a structurally distinct heparin-binding domain that targets and potentiates its actions. In addition, a finely tuned, bidirectional mechanism regulates when and where neuregulin is released from neurons in response to neurotrophic factors produced by both neuronal targets and supporting glial cells. Together, this produces a balanced intercellular signaling system that can be localized to distinct regions for both normal development and maintenance of the mature nervous system. Recent evidence suggests that neuregulin signaling plays important roles in many neurological disorders including multiple sclerosis, traumatic brain and spinal cord injury, peripheral neuropathy, and schizophrenia. Here, we review the basic biology of neuregulins and relate this to research suggesting their involvement with and potential therapeutic uses for neurological disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 45 | Neurosci. Lett. 2006 Mar 396: 117-20 |
| PMID | 16326006 |
| Title | Supportive evidence for neuregulin 1 as a susceptibility gene for schizophrenia in a Japanese population. |
| Abstract | schizophrenia is a complex genetic disorder and affects approximately 1% of the population worldwide. Recently, Stefansson et al. identified neuregulin 1 (NRG1) on 8p12 as a susceptibility gene for schizophrenia in the Icelandic population. It was reported that the at-risk haplotype ("Hapice") constructed from five SNPs and two microsatellite markers was found to be over-represented in patients with schizophrenia compared to controls. Since then several independent studies have supported the association of NRG1 with schizophrenia. We performed a case-control association study using the four SNPs in a Japanese sample. We genotyped three SNPs (SNP8NRG221533, SNP8NRG241930, and SNP8NRG243177) from Stefansson et al. and one SNP (rs1081062) located in intron 1 of NRG1. There were no significant differences in allele frequencies for each SNP between cases and controls, however, homozygotes of minor alleles in SNP8NRG241930, SNP8NRG243177, and rs1081062 were associated with an increased risk of schizophrenia (P=0.025, OR=4.14; P=0.041, OR=1.43; and P=0.0023, OR=3.06, respectively). Furthermore, the haplotype constructed from four SNPs shows a significant association with schizophrenia (permutation P=0.026). Our data support the hypothesis that NRG1 gene is a susceptibility gene for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 46 | Eur. J. Hum. Genet. 2006 Sep 14: 1037-43 |
| PMID | 16736033 |
| Title | A summary statistic approach to sequence variation in noncoding regions of six schizophrenia-associated gene loci. |
| Abstract | In order to explore the role of noncoding variants in the genetics of schizophrenia, we sequenced 27 kb of noncoding DNA from the gene loci RAC-alpha serine/threonine-protein kinase (AKT1), brain-derived neurotrophic factor (BDNF), dopamine receptor-3 (DRD3), dystrobrevin binding protein-1 (DTNBP1), neuregulin-1 (NRG1) and regulator of G-protein signaling-4 (RGS4) in 37 schizophrenia patients and 25 healthy controls. To compare the allele frequency spectrum between the two samples, we separately computed Tajima's D-value for each sample. The results showed a smaller Tajima's D-value in the case sample, pointing to an excess of rare variants as compared to the control sample. When randomly permuting the affection status of sequenced individuals, we observed a stronger decrease of Tajima's D in 2400 out of 100,000 permutations, corresponding to a P-value of 0.024 in a one-sided test. Thus, rare variants are significantly enriched in the schizophrenia sample, indicating the existence of disease-related sequence alterations. When categorizing the sequenced fragments according to their level of human-rodent conservation or according to their gene locus, we observed a wide range of diversity parameter estimates. Rare variants were enriched in conserved regions as compared to nonconserved regions in both samples. Nevertheless, rare variants remained more common among patients, suggesting an increased number of variants under purifying selection in this sample. Finally, we performed a heuristic search for the subset of gene loci, which jointly produces the strongest difference between controls and cases. This showed a more prominent role of variants from the loci AKT1, BDNF and RGS4. Taken together, our approach provides promising strategy to investigate the genetics of schizophrenia and related phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 47 | Schizophr. Res. 2006 Jun 84: 253-71 |
| PMID | 16632332 |
| Title | Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. |
| Abstract | Neurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 48 | Schizophr Bull 2006 Jan 32: 9-16 |
| PMID | 16319375 |
| Title | Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. |
| Abstract | It has been conventional for psychiatric research, including the search for predisposing genes, to proceed under the assumption that schizophrenia and bipolar disorder are separate disease entities with different underlying etiologies. These represent Emil Kraepelin's traditional dichotomous classification of the so-called "functional" psychoses and form the basis of modern diagnostic practice. However, findings emerging from many fields of psychiatric research do not fit well with this model. In particular, the pattern of findings emerging from genetic studies shows increasing evidence for an overlap in genetic susceptibility across the traditional classification categories-including association findings at DAOA(G72), DTNBP1 (dysbindin), COMT, BDNF, DISC1, and NRG1. The emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, DISC1 and NRG1 may confer susceptibility to a form of illness with mixed features of schizophrenia and mania. The elucidation of genotype-phenotype relationships is at an early stage, but current findings highlight the need to consider alternative approaches to classification and conceptualization for psychiatric research rather than continuing to rely heavily on the traditional Kraepelinian dichotomy. As psychosis susceptibility genes are identified and characterized over the next few years, this will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 49 | Proc. Natl. Acad. Sci. U.S.A. 2006 Aug 103: 12469-74 |
| PMID | 16891421 |
| Title | Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia. |
| Abstract | Abnormal oligodendrocyte function has been postulated as a primary etiological event in schizophrenia. Oligodendrocyte lineage transcription factor 2 (OLIG2) encodes a transcription factor central to oligodendrocyte development. Analysis of OLIG2 in a case-control sample (n = approximately 1,400) in the U.K. revealed several SNPs to be associated with schizophrenia (minimum P = 0.0001, gene-wide P = 0.0009). To obtain independent support for this association, we sought evidence for genetic interaction between OLIG2 and three genes of relevance to oligodendrocyte function for which we have reported evidence for association with schizophrenia: CNP, NRG1, and ERBB4. We found interaction effects on disease risk between OLIG2 and CNP (minimum P = 0.0001, corrected P = 0.008) for interaction with ERBB4 (minimum P = 0.002, corrected P = 0.04) but no evidence for interaction with NRG1. To investigate the biological plausibility of the interactions, we sought correlations between the expression of the genes. The results were similar to those of the genetic interaction analysis. OLIG2 expression significantly correlated in cerebral cortex with CNP (P < 10(-7)) and ERBB4 (P = 0.002, corrected P = 0.038) but not NRG1. In mouse striatum, Olig2 and Cnp expression also was correlated, and linkage analysis for trans-effects on gene expression suggests that each locus regulates the other's expression. Our data provide strong convergent evidence that variation in OLIG2 confers susceptibility to schizophrenia alone and as part of a network of genes implicated in oligodendrocyte function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 50 | Schizophr. Res. 2006 Sep 86: 1-14 |
| PMID | 16842972 |
| Title | Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability. |
| Abstract | Over 130 genes have been associated with schizophrenia in genetic studies. None of these has reached a sufficient level of confidence to be accepted as a universal susceptibility gene and problems of replicability suggest that many may be false positives. Nevertheless, these genes can be grouped into distinct families related to glutamate transmission (in particular related to NMDA receptor function), the control of synaptic plasticity, dopaminergic transmission, oxidative stress, glutathione and quinone metabolism and oligodendrocyte viability. These families mirror the processes disrupted in the schizophrenic brain and certain gene families can be linked together to form a clearly defined signalling cascade involved in the phenomenon of NMDA receptor-dependent long-term potentiation and synaptic plasticity, that may be interconnected with oligodendrocyte and oxidative stress-related pathways. Many of the protein products of these genes interact with each other, forming complex integrated networks. Certain high-interest genes (for example DISC1, NRG1, COMT) may exert multiple effects on different areas of these pathways, while others exert more specific effects on certain branches. The convergence of a large number of genes on a definable signaling network raises the possibility of numerous interactions between gene candidates, and suggests that a targeted multigenic pathway approach would be useful in gene association studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 51 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Mar 141B: 142-8 |
| PMID | 16402353 |
| Title | The involvement of ErbB4 with schizophrenia: association and expression studies. |
| Abstract | Neuregulin 1 (NRG1) has been found to be associated with schizophrenia in several populations. Consistently, mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. These observations raised the hypothesis that impaired NRG1-ErbB4 signaling may contribute to schizophrenia susceptibility. Nineteen SNPs encompassing the ErbB4 gene were selected from the HapMap database and genotyped in genomic DNA isolated from 59 Ashkenazi schizophrenia patients and 130 matched controls. Expression analysis of ErbB4 splice variants was performed on postmortem DLPFC samples obtained from Caucasian patients and controls by real-time PCR. We found a highly significant difference between patient and control groups in three SNPs from one linkage disequilibrium (LD) block both in allele (P = 0.013, 0.0045, 0.0049) and genotype frequencies (P = 0.00013, 0.000021, 0.00018), as well as a risk haplotype (P = 0.00044). Expression analysis indicated that the CYT-1 isoform is overexpressed in patients (P = 0.047) and that juxtamembrane (JM)-a displays a similar trend (P = 0.081). This study provides a direct link between ErbB4 and the disease. We propose that NRG1 and its receptor ErbB4 are components of a biological pathway, involved in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 52 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Jan 141B: 96-101 |
| PMID | 16249994 |
| Title | Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia. |
| Abstract | There is now strong evidence that Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. NRG1 mediates some of its effects through the tyrosine kinase receptor erbB4, and analysis of gene knock-out animals suggests that the functional interaction of NRG1 and erbB4 mediates behaviors that may model some aspects of the schizophrenia phenotype in mice. Given these findings, we have sought evidence for association between schizophrenia and erbB4. Mutation screening of erbB4 in 14 DSMIV schizophrenics revealed 15 SNPs, none of which were nonsynonymous. Analysis of the allele frequencies of each SNP in pools of 368 DSMIV schizophrenics and 368 controls provided modest evidence for association with two of the SNPs, although individual genotyping in an extended sample of 680 cases did not confirm this. However, we did find evidence for a significant interaction between the NRG1 "Icelandic" schizophrenia risk haplotype and erbB4 (P = 0.019). The NRG1 and erbB4 interacting marker was further genotyped in an independent sample of 290 cases and 634 controls from Dublin. Interaction between NRG1 and erbB4 remained significant in the combined sample of 970 cases and 1,341 controls, OR = 2.98 (CI: 1.16-7.64), P = 0.01, although it only showed a trend in the Dublin sample alone (P = 0.11, two tailed). Our data require independent replication, but tentatively suggest that NRG1 may mediate its effects on schizophrenia susceptibility through functional interaction with erbB4, and that genetic interaction between variants at the two loci increases susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 53 | Hum. Mol. Genet. 2006 Jun 15: 1995-2002 |
| PMID | 16687441 |
| Title | Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia. |
| Abstract | Chromosome 8p22-p11 has been identified as a locus for schizophrenia in several genome-wide scans and confirmed by meta-analysis of published linkage data. Systematic fine mapping using extended Icelandic pedigrees identified an associated haplotype in the gene neuregulin 1 (NRG1), also known as heuregulin, glial growth factor, NDF43 and ARIA. A 290 kb core at risk haplotype at the 5' end of the gene (HAP(ICE)), defined by five SNPs and two microsatellite polymorphisms was found to be associated with schizophrenia in the Icelandic and Scottish populations. A number of subsequent independent studies have attempted to replicate the association, and while some have been successful, the associated haplotype is not always HAP(ICE). Furthermore, no obviously functional or pathogenic variants have been identified, and the relationship between the gene and schizophrenia has remained inconclusive. To reconcile these conflicting findings and to give a comprehensive picture of the genetic architecture of this important gene, we performed a meta-analysis of 13 published population-based and family-based association studies up to November 2005. We analysed data from the SNP markers SNP8NRG241930, SNP8NRG243177, SNP8NRG221132 and SNP8NRG221533, and the microsatellite markers 478B14-848, 420M9-1395. Across these studies, strong positive association was found for all six polymorphisms. The haplotype analysis also showed significant association in the pooled international populations (OR=1.22, 95% CI 1.15-1.3, P=8 x 10(-10)). In Asian populations, the risk haplotype was focused around the two microsatellite markers, 478B14-848, 420M9-1395 (haplotype block B), and in Caucasian populations with the remaining four SNP markers (haplotype block A). This meta-analysis supports the involvement of NRG1 in the pathogenesis of schizophrenia, but with association between two different but adjacent haplotypes blocks in the Caucasian and Asian populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 54 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Apr 141B: 281-6 |
| PMID | 16526041 |
| Title | Linkage and association of schizophrenia with genetic variations in the locus of neuregulin 1 in Korean population. |
| Abstract | Chromosome 8p21-12 has been reported to be a susceptibility locus for schizophrenia based on genome-wide linkage scans. After neuregulin 1 (NRG1) was identified as a positional candidate gene for schizophrenia in this locus, several independent association studies have reported controversial results. To determine whether genetic variations in this locus are associated with schizophrenia in the Korean population, we investigated multiplex families and unrelated patients using linkage and association analyses. Seven microsatellite markers in 8p21-12 were genotyped for 40 families with schizophrenia, and a non-parametric linkage analysis was applied. The association study was performed with 242 unrelated schizophrenia patients and the same number of normal controls for three single nucleotide polymorphisms (SNPs), two microsatellite markers and their haplotypes. A significant linkage signal was observed on D8S1769, which is located 352 kb upstream of the 5' end of the first exon of NRG1 for two ("narrow" and "narrow with auditory hallucination (AH)") of the three adopted phenotype classes. In the association study, the G allele of SNP8NRG241930 was significantly in excess in the subgroup of patients with AHs. We also found haplotypes which were associated with schizophrenia with a protective effect. This study provides additional suggestive evidence for both the linkage and association of genetic variations on 8p12, a locus of NRG1, with schizophrenia. NRG1 might either play a role in the predisposition to schizophrenia or be in linkage disequilibrium (LD) with a causal locus of this illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 55 | Am. J. Hum. Genet. 2006 Feb 78: 315-33 |
| PMID | 16400611 |
| Title | Genomewide linkage scan of 409 European-ancestry and African American families with schizophrenia: suggestive evidence of linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the combined sample. |
| Abstract | We report the clinical characteristics of a schizophrenia sample of 409 pedigrees--263 of European ancestry (EA) and 146 of African American ancestry (AA)--together with the results of a genome scan (with a simple tandem repeat polymorphism interval of 9 cM) and follow-up fine mapping. A family was required to have a proband with schizophrenia (SZ) and one or more siblings of the proband with SZ or schizoaffective disorder. Linkage analyses included 403 independent full-sibling affected sibling pairs (ASPs) (279 EA and 124 AA) and 100 all-possible half-sibling ASPs (15 EA and 85 AA). Nonparametric multipoint linkage analysis of all families detected two regions with suggestive evidence of linkage at 8p23.3-q12 and 11p11.2-q22.3 (empirical Z likelihood-ratio score [Z(lr)] threshold >/=2.65) and, in exploratory analyses, two other regions at 4p16.1-p15.32 in AA families and at 5p14.3-q11.2 in EA families. The most significant linkage peak was in chromosome 8p; its signal was mainly driven by the EA families. Z(lr) scores >2.0 in 8p were observed from 30.7 cM to 61.7 cM (Center for Inherited Disease Research map locations). The maximum evidence in the full sample was a multipoint Z(lr) of 3.25 (equivalent Kong-Cox LOD of 2.30) near D8S1771 (at 52 cM); there appeared to be two peaks, both telomeric to neuregulin 1 (NRG1). There is a paracentric inversion common in EA individuals within this region, the effect of which on the linkage evidence remains unknown in this and in other previously analyzed samples. Fine mapping of 8p did not significantly alter the significance or length of the peak. We also performed fine mapping of 4p16.3-p15.2, 5p15.2-q13.3, 10p15.3-p14, 10q25.3-q26.3, and 11p13-q23.3. The highest increase in Z(lr) scores was observed for 5p14.1-q12.1, where the maximum Z(lr) increased from 2.77 initially to 3.80 after fine mapping in the EA families. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 56 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Jan 141B: 102-9 |
| PMID | 16287046 |
| Title | Analysis of polymorphisms in AT-rich domains of neuregulin 1 gene in schizophrenia. |
| Abstract | Linkage analysis and association studies have pointed to neuregulin 1 (NRG1) as the prime candidate for 8p-linked schizophrenia (SZ). However, so far, no specific functional alleles in the gene's exons, intron-exon junctions and promoters have been identified that are unequivocally associated with SZ. In this study, we analyzed several NRG1 polymorphisms that affect ATTT motifs and AT-rich regions of the gene. We have previously identified a number of such polymorphisms in the promoters of other SZ and bipolar disorder (BD) candidate genes and found positive associations to several of them. In addition, allele specific differences in the binding of brain proteins have been found for many of the polymorphisms. A case control design was used to compare allele frequencies in Caucasian and African American patients with SZ and controls. In the African American group, a significant difference was found in the allele and genotype distribution for several of the markers and haplotype blocks located in the 5'- and 3'-ends of the gene. The most significant result was obtained for rs6150532, an insertion/deletion variant in a conserved region of an intron that separates two small, alternatively spliced exons. Allele-specific and developmental differences were detected in the binding of a brain protein using newborn rat pups when probes containing the two rs6150532 alleles were used in electromobility gel shift assays. There were no significant differences in allele or genotype distribution found for any of the markers in the Caucasian sample. Although the samples size is relatively small, the findings support a role for NRG1 in SZ in African Americans and suggest that polymorphic differences in regions of the gene that recognize AT-binding proteins may be a factor in disease pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 57 | Mol. Psychiatry 2006 Jan 11: 66-75 |
| PMID | 16189508 |
| Title | Extreme population differences across Neuregulin 1 gene, with implications for association studies. |
| Abstract | Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia in recent years since its first association with the disease in an Icelandic population. Since then, many association studies have analysed allele and haplotype frequencies in distinct populations yielding varying results: some have replicated the association, although with different alleles or haplotypes being associated, whereas others have failed to replicate the association. These contradictory results might be attributed to population differences in allele and haplotype frequencies. In order to approach this issue, we have typed 13 SNPs across this large 1.4 Mb gene, including two of the SNPs originally found associated with schizophrenia in the Icelandic population, the objective being to discover if the underlying cause of the association discrepancies to date may be due to population-specific genetic variation. The analyses have been performed in a total of 1088 individuals from 39 populations, covering most of the genetic diversity in the human species. Most of the SNPs analysed displayed differing frequencies according to geographical region. These allele differences are especially relevant in two SNPs located in a large intron of the gene, as shown by the extreme F(ST) values, which reveal genetic stratification correlated to broad continental areas. This finding may be indicative of the influence of some local selective forces on this gene. Furthermore, haplotype analysis reveals a clear clustering according to geographical areas. In summary, our findings suggest that NRG1 presents extreme population differences in allele and haplotype frequencies. We have given recommendations for taking this into account in future association studies since this diversity could give rise to erroneous results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 58 | Schizophr. Res. 2006 Sep 86: 1-14 |
| PMID | 16842972 |
| Title | Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability. |
| Abstract | Over 130 genes have been associated with schizophrenia in genetic studies. None of these has reached a sufficient level of confidence to be accepted as a universal susceptibility gene and problems of replicability suggest that many may be false positives. Nevertheless, these genes can be grouped into distinct families related to glutamate transmission (in particular related to NMDA receptor function), the control of synaptic plasticity, dopaminergic transmission, oxidative stress, glutathione and quinone metabolism and oligodendrocyte viability. These families mirror the processes disrupted in the schizophrenic brain and certain gene families can be linked together to form a clearly defined signalling cascade involved in the phenomenon of NMDA receptor-dependent long-term potentiation and synaptic plasticity, that may be interconnected with oligodendrocyte and oxidative stress-related pathways. Many of the protein products of these genes interact with each other, forming complex integrated networks. Certain high-interest genes (for example DISC1, NRG1, COMT) may exert multiple effects on different areas of these pathways, while others exert more specific effects on certain branches. The convergence of a large number of genes on a definable signaling network raises the possibility of numerous interactions between gene candidates, and suggests that a targeted multigenic pathway approach would be useful in gene association studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 59 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Jan 141B: 96-101 |
| PMID | 16249994 |
| Title | Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia. |
| Abstract | There is now strong evidence that Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. NRG1 mediates some of its effects through the tyrosine kinase receptor erbB4, and analysis of gene knock-out animals suggests that the functional interaction of NRG1 and erbB4 mediates behaviors that may model some aspects of the schizophrenia phenotype in mice. Given these findings, we have sought evidence for association between schizophrenia and erbB4. Mutation screening of erbB4 in 14 DSMIV schizophrenics revealed 15 SNPs, none of which were nonsynonymous. Analysis of the allele frequencies of each SNP in pools of 368 DSMIV schizophrenics and 368 controls provided modest evidence for association with two of the SNPs, although individual genotyping in an extended sample of 680 cases did not confirm this. However, we did find evidence for a significant interaction between the NRG1 "Icelandic" schizophrenia risk haplotype and erbB4 (P = 0.019). The NRG1 and erbB4 interacting marker was further genotyped in an independent sample of 290 cases and 634 controls from Dublin. Interaction between NRG1 and erbB4 remained significant in the combined sample of 970 cases and 1,341 controls, OR = 2.98 (CI: 1.16-7.64), P = 0.01, although it only showed a trend in the Dublin sample alone (P = 0.11, two tailed). Our data require independent replication, but tentatively suggest that NRG1 may mediate its effects on schizophrenia susceptibility through functional interaction with erbB4, and that genetic interaction between variants at the two loci increases susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 60 | Schizophr. Res. 2007 Mar 91: 27-36 |
| PMID | 17300918 |
| Title | The role of DTNBP1, NRG1, and AKT1 in the genetics of schizophrenia in Finland. |
| Abstract | Several putative schizophrenia susceptibility genes have recently been identified. Significant associations between schizophrenia and neuregulin 1 (NRG1) and dysbindin (DTNBP1) were first reported in 2002 and studies in several populations have since independently reported positive associations to these gene regions. Further, both tentative functional and genetic data have implicated the role of AKT1 in the genetic background of this disorder. However, findings have not been consistent in all populations. We investigated the allelic diversity of these three genes NRG1, DTNBP1 and AKT1 in a representative nation-wide study sample of 441 Finnish schizophrenia families consisting of 865 affected individuals, in order to assess their role in one of the largest population-based study samples. DTNBP1 and AKT1 failed to show evidence of association, whereas two SNPs in the 3' region of the NRG1 gene yielded suggestive evidence of association (p=0.012 and p=0.048) in family-based association analyses. Thus, our study does not indicate that AKT1 or DTNBP1 play a role in the etiology of schizophrenia in the Finnish population. Furthermore, results do not support a major role for NRG1, but we cannot completely exclude a minor role of this gene in the Finnish population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 61 | Neurosci. Res. 2007 Apr 57: 574-8 |
| PMID | 17275115 |
| Title | No association between the ERBB3 gene and schizophrenia in a Japanese population. |
| Abstract | There is cumulative evidence that neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. Postmortem studies on brains from schizophrenia patients have revealed changes in the mRNA expression levels of v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3), one of the NRG1 receptor genes. These observations suggest that NRG1-ERBB signaling is involved in the pathogenesis of schizophrenia. To assess whether the ERBB3 gene could be implicated in vulnerability to schizophrenia, we conducted a case-control (399 patients and 438 controls) association study in Japanese subjects. There were no significant association between the polymorphisms or haplotypes of ERBB3 and schizophrenia. The present study shows that ERBB3 does not play a major role in conferring susceptibility to schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 62 | Neuron 2007 May 54: 599-610 |
| PMID | 17521572 |
| Title | Neuregulin-1 enhances depolarization-induced GABA release. |
| Abstract | Neuregulin-1 (NRG1), a regulator of neural development, has been shown to regulate neurotransmission at excitatory synapses. Although ErbB4, a key NRG1 receptor, is expressed in glutamic acid decarboxylase (GAD)-positive neurons, little is known about its role in GABAergic transmission. We show that ErbB4 is localized at GABAergic terminals of the prefrontal cortex. Our data indicate a role of NRG1, both endogenous and exogenous, in regulation of GABAergic transmission. This effect was blocked by inhibition or mutation of ErbB4, suggesting the involvement of ErbB4. Together, these results indicate that NRG1 regulates GABAergic transmission via presynaptic ErbB4 receptors, identifying a novel function of NRG1. Because both NRG1 and ErbB4 have emerged as susceptibility genes of schizophrenia, these observations may suggest a mechanism for abnormal GABAergic neurotransmission in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 63 | Neuron 2007 May 54: 583-97 |
| PMID | 17521571 |
| Title | The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity. |
| Abstract | Neuregulin-1 (NRG1) signaling participates in numerous neurodevelopmental processes. Through linkage analysis, NRG1 has been associated with schizophrenia, although its pathophysiological role is not understood. The prevailing models of schizophrenia invoke hypofunction of the glutamatergic synapse and defects in early development of hippocampal-cortical circuitry. Here, we show that the erbB4 receptor, as a postsynaptic target of NRG1, plays a key role in activity-dependent maturation and plasticity of excitatory synaptic structure and function. Synaptic activity leads to the activation and recruitment of erbB4 into the synapse. Overexpressed erbB4 selectively enhances AMPA synaptic currents and increases dendritic spine size. Preventing NRG1/erbB4 signaling destabilizes synaptic AMPA receptors and leads to loss of synaptic NMDA currents and spines. Our results indicate that normal activity-driven glutamatergic synapse development is impaired by genetic deficits in NRG1/erbB4 signaling leading to glutamatergic hypofunction. These findings link proposed effectors in schizophrenia: NRG1/erbB4 signaling perturbation, neurodevelopmental deficit, and glutamatergic hypofunction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 64 | Neuron 2007 May 54: 495-7 |
| PMID | 17521560 |
| Title | NRG1 and synaptic function in the CNS. |
| Abstract | Recent genetic evidence indicates that neuregulin 1 (NRG1) and its receptor erbB4 may be susceptibility genes in schizophrenia, but their function in CNS synaptic transmission and circuitry is not well understood. In this issue of Neuron, studies from Li et al. and Woo et al. show that NRG1 and erbB4 regulate transmission at brain glutamate and GABA synapses. These findings raise the possibility of synaptic defects in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 65 | Proc. Natl. Acad. Sci. U.S.A. 2007 May 104: 8131-6 |
| PMID | 17483467 |
| Title | Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. |
| Abstract | Several psychiatric disorders are associated with white matter defects, suggesting that oligodendrocyte (OL) abnormalities underlie some aspects of these diseases. Neuregulin 1 (NRG1) and its receptor, erbB4, are genetically linked with susceptibility to schizophrenia and bipolar disorder. In vitro studies suggest that NRG1-erbB signaling is important for OL development. To test whether erbB signaling contributes to psychiatric disorders by regulating the structure or function of OLs, we analyzed transgenic mice in which erbB signaling is blocked in OLs in vivo. Here we show that loss of erbB signaling leads to changes in OL number and morphology, reduced myelin thickness, and slower conduction velocity in CNS axons. Furthermore, these transgenic mice have increased levels of dopamine receptors and transporters and behavioral alterations consistent with neuropsychiatric disorders. These results indicate that defects in white matter can cause alterations in dopaminergic function and behavior relevant to neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 66 | Expert Rev Neurother 2007 Jan 7: 29-31 |
| PMID | 17187494 |
| Title | Schizophrenia: more evidence for less glutamate. |
| Abstract | Evaluation of: Hahn CJ, Hoau-Yan W, Dan-Sung C et al. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat. Med. 12, 824-828 (2006). schizophrenia may be associated with deficits in glutamate transmission at the N-methyl-D-aspartate (NMDA) receptor complex. Recent work has shown that neuregulin 1 (NRG1) acts via ErbB4 receptors to inhibit NMDA receptor currents. This is important given that NRG1 is a convincing susceptibility gene in schizophrenia. Hahn and colleagues add to our knowledge of NRG1 modulation of NMDA receptors and show intriguing differences between control and schizophrenic brains. NMDA receptors in the schizophrenic prefrontal cortex showed smaller responses to exogenously applied NMDA/glycine. Furthermore, NMDA receptors in tissue from schizophrenic patients appeared to be more sensitive to the inhibitory effects of a fixed dose of NRG1. In agreement, the ErbB4-PSD-95-NMDA complex was more tightly coupled in schizophrenic brains and NRG1-mediated stimulation of ErbB4 was markedly enhanced. These findings underscore the importance of NMDA receptors in schizophrenia and support therapeutic strategies aimed at boosting glutamate transmission. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 67 | BMC Psychiatry 2007 -1 7: 21 |
| PMID | 17519028 |
| Title | The NRG1 exon 11 missense variant is not associated with autism in the Central Valley of Costa Rica. |
| Abstract | We are conducting a genetic study of autism in the isolated population of the Central Valley of Costa Rica (CVCR). A novel Neuregulin 1 (NRG1) missense variant (exon 11 G>T) was recently associated with psychosis and schizophrenia (SCZ) in the same population isolate. We genotyped the NRG1 exon 11 missense variant in 146 cases with autism, or autism spectrum disorder, with CVCR ancestry, and both parents when available (N = 267 parents) from 143 independent families. Additional microsatellites were genotyped to examine haplotypes bearing the exon 11 variant. The NRG1 exon 11 G>T variant was found in 4/146 cases including one de novo occurrence. The frequency of the variant in case chromosomes was 0.014 and 0.045 in the parental non-transmitted chromosomes. At least 6 haplotypes extending 0.229 Mb were associated with the T allele. Three independent individuals, with no personal or family history of psychiatric disorder, shared at least a 1 megabase haplotype 5' to the T allele. The NRG1 exon 11 missense variant is not associated with autism in the CVCR. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 68 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Oct 144B: 954-7 |
| PMID | 17503451 |
| Title | Family-based association study of neuregulin-1 gene and psychosis in a Spanish sample. |
| Abstract | Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia since its first association with the disorder in an Icelandic population. Since then, many studies have analyzed allele and haplotype frequencies in European and Asian populations in cases and controls yielding varying results. We investigated the association of NRG1 with psychosis in a total sample set of 575 individuals from 151 Spanish nuclear families. We tested eight SNPs across 1.2 Mb along NRG1 including regions previously associated to schizophrenia in association studies. After correction for multiple testing, the TDT analysis for each marker did not show a significant over-transmission of alleles from the parents to the affected offspring for any of the markers (P > 0.05). The haplotypic analysis with TRANSMIT and PDT did not show preferential transmission for any of the haplotypes analyzed in our sample. These results do not seem to suggest that the investigated NRG1 markers play a role in schizophrenia in the Spanish population, although the finding of a trend for association with one SNP in the 3'of the gene warrants further investigation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 69 | Hum. Genet. 2007 Jul 121: 759-62 |
| PMID | 17457614 |
| Title | Extreme individual marker F(ST )values do not imply population-specific selection in humans: the NRG1 example. |
| Abstract | Extreme population differentiation, as measured by the F(ST) value, has been suggested as an indicator of recent population-specific positive selection. Elevated F(ST) values indicating high differentiation between continental groups were previously reported on a linkage disequilibrium region in the Neuregulin 1 gene, a gene which has been associated to schizophrenia. In the present study we show evidence that high F(ST) values may not necessarily imply the action of selection, in particular positive selection, neither globally nor regionally, using the example of the NRG1 gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 70 | Mol. Psychiatry 2007 Oct 12: 946-57 |
| PMID | 17440436 |
| Title | Neuregulin1-induced cell migration is impaired in schizophrenia: association with neuregulin1 and catechol-o-methyltransferase gene polymorphisms. |
| Abstract | Neuregulin1 (NRG1), a candidate susceptibility gene for schizophrenia, plays a critical role in neuronal migration and central nervous system development. However, its relation to schizophrenia pathogenesis is unknown. Here we show that B lymphoblasts migrate to NRG1 through the ErbB-signaling system as observed in neuronal cells. We assessed NRG1-induced cell migration in B lymphoblasts from patients with schizophrenia and found that NRG1-induced migration is significantly decreased compared with control individuals in two independent cohorts. This impaired migration is related at least in part to reduced AKT phosphorylation in the patients. Moreover, the magnitude of NRG1-induced migration is associated with polymorphisms of the NRG1 and catechol-o-methyltransferase genes and with an epistatic interaction of these genes. This study demonstrates that the migratory response of schizophrenia-derived cells to NRG1 is impaired and is associated with genetic variations in more than one schizophrenia susceptibility gene, providing a novel insight into potential neurodevelopmental mechanisms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 71 | Expert Rev Neurother 2007 Jan 7: 29-31 |
| PMID | 17187494 |
| Title | Schizophrenia: more evidence for less glutamate. |
| Abstract | Evaluation of: Hahn CJ, Hoau-Yan W, Dan-Sung C et al. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat. Med. 12, 824-828 (2006). schizophrenia may be associated with deficits in glutamate transmission at the N-methyl-D-aspartate (NMDA) receptor complex. Recent work has shown that neuregulin 1 (NRG1) acts via ErbB4 receptors to inhibit NMDA receptor currents. This is important given that NRG1 is a convincing susceptibility gene in schizophrenia. Hahn and colleagues add to our knowledge of NRG1 modulation of NMDA receptors and show intriguing differences between control and schizophrenic brains. NMDA receptors in the schizophrenic prefrontal cortex showed smaller responses to exogenously applied NMDA/glycine. Furthermore, NMDA receptors in tissue from schizophrenic patients appeared to be more sensitive to the inhibitory effects of a fixed dose of NRG1. In agreement, the ErbB4-PSD-95-NMDA complex was more tightly coupled in schizophrenic brains and NRG1-mediated stimulation of ErbB4 was markedly enhanced. These findings underscore the importance of NMDA receptors in schizophrenia and support therapeutic strategies aimed at boosting glutamate transmission. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 72 | PLoS ONE 2007 -1 2: e1369 |
| PMID | 18159252 |
| Title | Neuregulin-1 regulates cell adhesion via an ErbB2/phosphoinositide-3 kinase/Akt-dependent pathway: potential implications for schizophrenia and cancer. |
| Abstract | Neuregulin-1 (NRG1) is a putative schizophrenia susceptibility gene involved extensively in central nervous system development as well as cancer invasion and metastasis. Using a B lymphoblast cell model, we previously demonstrated impairment in NRG1alpha-mediated migration in cells derived from patients with schizophrenia as well as effects of risk alleles in NRG1 and catechol-O-methyltransferase (COMT), a second gene implicated both in schizophrenia susceptibility and in cancer. Here, we examine cell adhesion, an essential component process of cell motility, using an integrin-mediated cell adhesion assay based on an interaction between ICAM-1 and the CD11a/CD18 integrin heterodimer expressed on lymphoblasts. In our assay, NRG1alpha induces lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. The maximum range of variation in adhesion over sixty minutes correlates strongly with NRG1alpha-induced migration (r(2) = 0.61). NRG1alpha-induced adhesion variation is blocked by erbB2, PI3K, and Akt inhibitors, but not by PLC, ROCK, MLCK, or MEK inhibitors, implicating the erbB2/PI3K/Akt1 signaling pathway in NRG1-stimulated, integrin-mediated cell adhesion. In cell lines from 20 patients with schizophrenia and 20 normal controls, cells from patients show a significant deficiency in the range of NRG1alpha-induced adhesion (p = 0.0002). In contrast, the response of patient-derived cells to phorbol myristate acetate is unimpaired. The COMT Val108/158Met genotype demonstrates a strong trend towards predicting the range of the NRG1alpha-induced adhesion response with risk homozygotes having decreased variation in cell adhesion even in normal subjects (p = 0.063). Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 73 | Cell. Physiol. Biochem. 2007 -1 20: 687-702 |
| PMID | 17982252 |
| Title | Molecular mechanisms of schizophrenia. |
| Abstract | schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 74 | Schizophr Bull 2007 Nov 33: 1343-53 |
| PMID | 17329232 |
| Title | eIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia? |
| Abstract | Bipolar disorder and schizophrenia share common chromosomal susceptibility loci and many risk-promoting genes. Oligodendrocyte cell loss and hypomyelination are common to both diseases. A number of environmental risk factors including famine, viral infection, and prenatal or childhood stress may also predispose to schizophrenia or bipolar disorder. In cells, related stressors (starvation, viruses, cytokines, oxidative, and endoplasmic reticulum stress) activate a series of eIF2-alpha kinases, which arrest protein synthesis via the eventual inhibition, by phosphorylated eIF2-alpha, of the translation initiation factor eIF2B. Growth factors increase protein synthesis via eIF2B activation and counterbalance this system. The control of protein synthesis by eIF2-alpha kinases is also engaged by long-term potentiation and repressed by long-term depression, mediated by N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors. Many genes reportedly associated with both schizophrenia and bipolar disorder code for proteins within or associated with this network. These include NMDA (GRIN1, GRIN2A, GRIN2B) and metabotropic (GRM3, GRM4) glutamate receptors, growth factors (BDNF, NRG1), and many of their downstream signaling components or accomplices (AKT1, DAO, DAOA, DISC1, DTNBP1, DPYSL2, IMPA2, NCAM1, NOS1, NOS1AP, PIK3C3, PIP5K2A, PDLIM5, RGS4, YWHAH). They also include multiple gene products related to the control of the stress-responsive eIF2-alpha kinases (IL1B, IL1RN, MTHFR, TNF, ND4, NDUFV2, XBP1). Oligodendrocytes are particularly sensitive to defects in the eIF2B complex, mutations in which are responsible for vanishing white matter disease. The convergence of natural and genetic risk factors on this area in bipolar disorder and schizophrenia may help to explain the apparent vulnerability of this cell type in these conditions. This convergence may also help to reconcile certain arguments related to the importance of nature and nurture in the etiology of these psychiatric disorders. Both may affect common stress-related signaling pathways that dictate oligodendrocyte viability and synaptic plasticity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 75 | Psychiatry Clin. Neurosci. 2007 Feb 61: 3-19 |
| PMID | 17239033 |
| Title | Molecular genetics of bipolar disorder and depression. |
| Abstract | In this review, all papers relevant to the molecular genetics of bipolar disorder published from 2004 to the present (mid 2006) are reviewed, and major results on depression are summarized. Several candidate genes for schizophrenia may also be associated with bipolar disorder: G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Of these, association with G72 may be most robust. However, G72 haplotypes and polymorphisms associated with bipolar disorder are not consistent with each other. The positional candidate approach showed an association between bipolar disorder and TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHMP1.5 (18p11.2), GCHI (14q22-24), MLC1 (22q13), GABRA5 (15q11-q13), BCR (22q11), CUX2, FLJ32356 (12q23-q24), and NAPG (18p11). Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation. From gene expression analysis, PDLIM5, somatostatin, and the mtDNA 3243 mutation were found to be related to bipolar disorder. Whereas most previous positive findings were not supported by subsequent studies, DRD1 and IMPA2 have been implicated in follow-up studies. Several candidate genes in the circadian rhythm pathway, BmaL1, TIMELESS, and PERIOD3, are reported to be associated with bipolar disorder. Linkage studies show many new linkage loci. In depression, the previously reported positive finding of a gene-environmental interaction between HTTLPR (insertion/deletion polymorphism in the promoter of a serotonin transporter) and stress was not replicated. Although the role of the TPH2 mutation in depression had drawn attention previously, this has not been replicated either. Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5. New technologies for comprehensive genomic analysis have already been applied. HTTLPR and BDNF promoter polymorphisms are now found to be more complex than previously thought, and previous papers on these polymorphisms should be treated with caution. Finally, this report addresses some possible causes for the lack of replication in this field. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 76 | Int. Rev. Neurobiol. 2007 -1 78: 327-76 |
| PMID | 17349866 |
| Title | Involvement of neuropeptide systems in schizophrenia: human studies. |
| Abstract | Neuropeptides are heterogeneously distributed throughout the digestive, circulatory, and nervous systems and serve as neurotransmitters, neuromodulators, and hormones. Neuropeptides are phylogenetically conserved and have been demonstrated to regulate numerous behaviors. They have been hypothesized to be pathologically involved in several psychiatric disorders, including schizophrenia. On the basis of preclinical data, numerous studies have sought to examine the role of neuropeptide systems in schizophrenia. This chapter reviews the clinical data, linking alterations in neuropeptide systems to the etiology, pathophysiology, and treatment of schizophrenia. Data for the following neuropeptide systems are included: arginine-vasopressin, cholecystokinin (CCK), corticotropin-releasing factor (CRF), interleukins, neuregulin 1 (NRG1), neurotensin (NT), neuropeptide Y (NPY), opioids, secretin, somatostatin, tachykinins, thyrotropin-releasing hormone (TRH), and vasoactive intestinal peptide (VIP). Data from cerebrospinal fluid (CSF), postmortem and genetic studies, as well as clinical trials are described. Despite the inherent difficulties associated with human studies (including small sample size, variable duration of illness, medication status, the presence of comorbid psychiatric disorders, and diagnostic heterogeneity), several findings are noteworthy. Postmortem studies support disease-related alterations in several neuropeptide systems in the frontal and temporal cortices. The strongest genetic evidence supporting a role for neuropeptides in schizophrenia are those studies linking polymorphisms in NRG1 and the CCKA receptor with schizophrenia. Finally, the only compounds that act directly on neuropeptide systems that have demonstrated therapeutic efficacy in schizophrenia are neurokinin receptor antagonists. Clearly, additional investigation into the role of neuropeptide systems in the etiology, pathophysiology, and treatment of schizophrenia is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 77 | Neurosci Biobehav Rev 2007 -1 31: 60-78 |
| PMID | 16782199 |
| Title | Susceptibility genes for schizophrenia: characterisation of mutant mouse models at the level of phenotypic behaviour. |
| Abstract | A wealth of evidence indicates that schizophrenia is heritable. However, the genetic mechanisms involved are poorly understood. Furthermore, it may be that genes conferring susceptibility interact with one another and with non-genetic factors to modulate risk status and/or the expression of symptoms. Genome-wide scanning and the mapping of several regions linked with risk for schizophrenia have led to the identification of several putative susceptibility genes including neuregulin-1 (NRG1), dysbindin (DTNBP1), regulator of G-protein signalling 4 (RGS4), catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH) and disrupted-in-schizophrenia 1 (DISC1). Genetic animal models involving targeted mutation via gene knockout or transgenesis have the potential to inform on the role of a given susceptibility gene on the development and behaviour of the whole organism and on whether disruption of gene function is associated with schizophrenia-related structural and functional deficits. This review focuses on data regarding the behavioural phenotype of mice mutant for schizophrenia susceptibility genes identified by positional candidate analysis and the study of chromosomal abnormalities. We also consider methodological issues that are likely to influence phenotypic effects, as well as the limitations associated with existing molecular techniques. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 78 | J. Biol. Chem. 2007 Aug 282: 24343-51 |
| PMID | 17565985 |
| Title | Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia. |
| Abstract | Neuregulin 1 (NRG1) is essential for the development and function of multiple organ systems, and its dysregulation has been linked to diseases such as cancer and schizophrenia. Recently, altered expression of a novel isoform (type IV) in the brain has been associated with schizophrenia-related genetic variants, especially rs6994992 (SNP8NRG243177). Here we have isolated and characterized full-length NRG1 type IV cDNAs from the adult and fetal human brain and identified novel splice variants of NRG1. Full-length type IV spans 1.8 kb and encodes a putative protein of 590 amino acids with a predicted molecular mass of approximately 66 kDa. The transcript consists of 11 exons with an Ig-like domain, an epidermal growth factor-like (EGF) domain, a beta-stalk, a transmembrane domain, and a cytoplasmic "a-tail," placing it in the beta1a NRG1 subclass. NRG1 type IV was not detected in any tissues except brain and a putative type IV NRG1 protein of 66 kDa was similarly brain-specific. Type IV transcripts are more abundantly expressed in the fetal brain, where, in addition to the full-length structure, two novel type IV variants were identified. In vitro luciferase-reporter assays demonstrate that the 5' promoter region upstream of type IV is functional, with differential activity associated with genetic variation at rs6994992, and that promoter competition may impact on type IV expression. Our data suggest that type IV is a unique brain-specific NRG1 that is differentially expressed and processed during early development, is translated, and its expression regulated by a schizophrenia risk-associated functional promoter or single nucleotide polymorphism (SNP). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 79 | Adv Anat Embryol Cell Biol 2007 -1 190: 1-65 |
| PMID | 17432114 |
| Title | The neuregulin-I/ErbB signaling system in development and disease. |
| Abstract | Neuregulins (NRGs) comprise a large family of EGF-like signaling molecules involved in cell-cell communication during development and disease. The neuregulin family of ligands has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins. In contrast, the NRG1 proteins have been demonstrated to play important roles during the development of the nervous system, heart, and mammary glands. For example, NRG1 has essential functions in the development of neural crest cells and some of their major derivatives, like Schwann cells and sympathetic neurons. NRG1 controls the trabeculation of the myocardial musculature and the ductal differentiation of the mammary epithelium. Moreover, there is emerging evidence for the involvement of NRG signals in the development and function of several other organ systems, and in human disease, including breast cancer and schizophrenia. Many different isoforms of the Neuregulin-1 gene are synthesized. Such isoforms differ in their tissue-specific expression patterns and their biological activities, thereby contributing to the great diversity of the in vivo functions of NRG1. Neuregulins transmit their signals to target cells by interacting with transmembrane tyrosine kinase receptors of the ErbB family. This family includes four members, the epidermal growth factor receptor (EGF-R, ErbB1, ErbB2, ErbB3, and ErbB4). Receptor-ligand interaction induces the heterodimerization of receptor monomers, which in turn results in the activation of intracellular signaling cascades and the induction of cellular responses including proliferation, migration, differentiation, and survival or apoptosis. In vivo, functional NRG1 receptors are heterodimers composed of ErbB2 with either an ErbB3, or ErbB4 molecule. The tissue-specific distribution of the different receptor types further contributes to the diversity and specificity of the biological functions of this signaling pathway. It is a typical feature of the Neuregulin-1/ErbB signaling pathway to control sequential steps during the development of a particular organ system. For example, this pathway functions in early precursor proliferation, maturation, as well as in the myelination of Schwann cells. The systematic analysis of genetic models that have been established by the help of conventional as well as conditional gene targeting strategies in mice was instrumental for the uncovering of the multitude of biological functions of this signaling system. In this review the basic biology of the Neuregulin-1/ErbB system and how it relates to the in vivo functions were discussed with special emphasis to transgenic techniques in mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 80 | Behav Brain Funct 2007 -1 3: 31 |
| PMID | 17598910 |
| Title | Interactions among genes in the ErbB-Neuregulin signalling network are associated with increased susceptibility to schizophrenia. |
| Abstract | Evidence of genetic association between the NRG1 (Neuregulin-1) gene and schizophrenia is now well-documented. Furthermore, several recent reports suggest association between schizophrenia and single-nucleotide polymorphisms (SNPs) in ERBB4, one of the receptors for Neuregulin-1. In this study, we have extended the previously published associations by investigating the involvement of all eight genes from the ERBB and NRG families for association with schizophrenia. Eight genes from the ERBB and NRG families were tested for association to schizophrenia using a collection of 396 cases and 1,342 blood bank controls ascertained from Aberdeen, UK. A total of 365 SNPs were tested. Association testing of both alleles and genotypes was carried out using the fast Fisher's Exact Test (FET). To understand better the nature of the associations, all pairs of SNPs separated by >or= 0.5 cM with at least nominal evidence of association (P < 0.10) were tested for evidence of pairwise interaction by logistic regression analysis. 42 out of 365 tested SNPs in the eight genes from the ERBB and NRG gene families were significantly associated with schizophrenia (P < 0.05). Associated SNPs were located in ERBB4 and NRG1, confirming earlier reports. However, novel associations were also seen in NRG2, NRG3 and EGFR. In pairwise interaction tests, clear evidence of gene-gene interaction was detected for NRG1-NRG2, NRG1-NRG3 and EGFR-NRG2, and suggestive evidence was also seen for ERBB4-NRG1, ERBB4-NRG2, ERBB4-NRG3 and ERBB4-ERBB2. Evidence of intragenic interaction was seen for SNPs in ERBB4. These new findings suggest that observed associations between NRG1 and schizophrenia may be mediated through functional interaction not just with ERBB4, but with other members of the NRG and ERBB families. There is evidence that genetic interaction among these loci may increase susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 81 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jan 144B: 113-6 |
| PMID | 16958035 |
| Title | Schizophrenia is not associated with the functional candidate gene ERBB3: results from a case-control study. |
| Abstract | Increasing evidence has supported the hypothesis of a neurodevelopmental component in the etiology of schizophrenia. Recently, several independent microarray gene expression studies have revealed downregulated expression of myelin-related genes in the postmortem brains of schizophrenia patients. Complete myelination of the cortex has been observed to occur in late adolescence and early adulthood, which is typically the age of onset of schizophrenia. ERBB3 is a gene which has not only been found to be downregulated in schizophrenia simultaneously in three microarray studies, but also is a strong candidate because of its potential role in neurodevelopment as a receptor of NRG1. Therefore, we performed association analysis of seven nonsynonymous SNPs in this gene. Two SNPs in ERBB3 (rs773123 and rs2271188) were polymorphic in our samples, neither of which showed significant evidence of association with the illness (P = 0.639 and 0.561, respectively). Because replication across such studies is notoriously difficult, the microarray evidence implicating ERBB3 still strongly supports some role of this gene in schizophrenia. However, our failure to find genetic association suggests that the differential expression of ERBB3 in schizophrenia may be environmentally driven, or involve cis- or trans-acting genetic factors beyond the boundaries of the gene itself. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 82 | J. Neurosci. 2007 Apr 27: 4519-29 |
| PMID | 17460065 |
| Title | Neuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: differential synaptic function in NRG1+/- knock-outs compared with wild-type mice. |
| Abstract | We previously identified Neuregulin1 (NRG1) as a gene contributing to the risk of developing schizophrenia. Furthermore, we showed that NRG1+/- mutant mice display behavioral abnormalities that are reversed by clozapine, an atypical antipsychotic drug used for the treatment of schizophrenia. We now present evidence that ErbB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4), the tyrosine kinase receptor for NRG1 in hippocampal neurons, interacts with two nonreceptor tyrosine kinases, Fyn and Pyk2 (proline-rich tyrosine kinase 2). NRG1 stimulation of cells expressing ErbB4 and Fyn leads to the association of Fyn with ErbB4 and consequent activation. Furthermore, we show that NRG1 signaling, through activation of Fyn and Pyk2 kinases, stimulates phosphorylation of Y1472 on the NR2B subunit of the NMDA receptor (NMDAR), a key regulatory site that modulates channel properties. NR2B Y1472 is hypophosphorylated in NRG1+/- mutant mice, and this defect can be reversed by clozapine at a dose that reverses their behavioral abnormalities. We also demonstrate that short-term synaptic plasticity is altered and theta-burst long-term potentiation is impaired in NRG1+/- mutant mice, and incubation of hippocampal slices from these mice with NRG1 reversed those effects. Attenuated NRG1 signaling through ErbB4 may contribute to the pathophysiology of schizophrenia through dysfunction of NMDAR modulation. Thus, our data support the glutamate hypothesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 83 | Hum. Mol. Genet. 2007 Jan 16: 129-41 |
| PMID | 17164265 |
| Title | Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia. |
| Abstract | The neuregulin 1 (NRG1) receptor, ErbB4, has been identified as a potential risk gene for schizophrenia. HER4/ErbB4 is a receptor tyrosine kinase whose transcript undergoes alternative splicing in the brain. Exon 16 encodes isoforms containing a metalloprotease cleavable extracellular domain (JM-a), exon 15 for a cleavage resistant form (JM-b) and exon 26 for a cytoplasmic domain (CYT-1) with a phosphotidylinositol-3 kinase (PI3K) binding site. Disease-associated variants in the ErbB4 gene are intronic and implicate altered splicing of the gene. We examined ErbB4 splice-variant gene expression in the hippocampus and dorsolateral prefrontal cortex (DLPFC) in schizophrenia using qPCR and investigated whether expression levels are associated with previously reported genomic risk variants in ErbB4 in a large cohort of human brains. In the DLPFC, we confirmed previous observations, in a separate cohort, that mRNA for ErbB4 splice isoforms containing exon 16 (JM-a) and exon 26 (CYT-1) are significantly elevated in patients with schizophrenia. A main effect of genotype was observed in the DLPFC and hippocampus at a single risk SNP located in intron 12 (rs4673628) on isoforms containing exon 16 (JM-a). We also found that three intronic risk SNPs (rs7598440, rs707284, rs839523) and a core-risk haplotype surrounding exon 3 are strongly associated with elevated expression of splice variants containing exon 26 (CYT-1). These findings suggest that dysregulation of splice-variant specific expression of ErbB4 in the brain underlies the genetic association of the gene with schizophrenia and that the NRG1/ErbB4 signaling pathway may be an important genetic network involved in the pathogenesis of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 84 | Mol. Psychiatry 2007 Feb 12: 195-205 |
| PMID | 17033632 |
| Title | Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories. |
| Abstract | Childhood-onset schizophrenia (COS), defined as onset of psychosis by the age of 12, is a rare and malignant form of the illness, which may have more salient genetic influence. Since the initial report of association between neuregulin 1 (NRG1) and schizophrenia in 2002, numerous independent replications have been reported. In the current study, we genotyped 56 markers (54 single-nucleotide polymorphisms (SNPs) and two microsatellites) spanning the NRG1 locus on 78 COS patients and their parents. We used family-based association analysis for both diagnostic (extended transmission disequilibrium test) and quantitative phenotypes (quantitative transmission disequilibrium test) and mixed-model regression. Most subjects had prospective anatomic brain magnetic resonance imaging (MRI) scans at 2-year intervals. Further, we genotyped a sample of 165 healthy controls in the MRI study to examine genetic risk effects on normal brain development. Individual markers showed overtransmission of alleles to affecteds (P=0.009-0.05). Further, several novel four-marker haplotypes demonstrated significant transmission distortion. There was no evidence of epistasis with SNPs in erbB4. The risk allele (0) at 420M9-1395 was associated with poorer premorbid social functioning. Further, possession of the risk allele was associated with different trajectories of change in lobar volumes. In the COS group, risk allele carriers had greater total gray and white matter volume in childhood and a steeper rate of subsequent decline in volume into adolescence. By contrast, in healthy children, possession of the risk allele was associated with different trajectories in gray matter only and was confined to frontotemporal regions, reflecting epistatic or other illness-specific effects mediating NRG1 influence on brain development in COS. This replication further documents the role of NRG1 in the abnormal brain development in schizophrenia. This is the first demonstration of a disease-specific pattern of gene action in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 85 | Neuroscience 2007 Nov 149: 861-70 |
| PMID | 17905522 |
| Title | Heterozygous neuregulin 1 mice display greater baseline and Delta(9)-tetrahydrocannabinol-induced c-Fos expression. |
| Abstract | Cannabis use may increase the risk of developing schizophrenia by precipitating the disorder in genetically vulnerable individuals. Neuregulin 1 (NRG1) is a schizophrenia susceptibility gene and mutant mice heterozygous for the transmembrane domain of this gene (NRG1 HET mice) exhibit a schizophrenia-related phenotype. We have recently shown that NRG1 HET mice are more sensitive to the behavioral effects of the main psychoactive constituent of cannabis, Delta(9)-tetrahydrocannabinol (THC). In the present study, we examined the effects of THC (10 mg/kg i.p.) on neuronal activity in NRG1 HET mice and wild type-like (WT) mice using c-Fos immunohistochemistry. In the lateral septum, THC selectively increased c-Fos expression in NRG1 HET mice with no corresponding effect being observed in WT mice. In addition, THC promoted a greater increase in c-Fos expression in NRG1 HET mice than WT mice in the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the paraventricular nucleus of the hypothalamus. Consistent with NRG1 HET mice exhibiting a schizophrenia-related phenotype, these mice expressed greater drug-free levels of c-Fos in two regions thought to be involved in schizophrenia, the shell of the nucleus accumbens and the lateral septum. Interestingly, the effects of genotype on c-Fos expression, drug-free or following THC exposure, were only observed when animals experienced behavioral testing prior to perfusion. This suggests an interaction with stress was necessary for the promotion of these effects. These data provide neurobiological correlates for the enhanced behavioral sensitivity of NRG1 HET mice to THC and reinforce the existence of cannabinoid-neuregulin 1 interactions in the CNS. This research may enhance our understanding of how genetic factors increase individual vulnerability to schizophrenia and cannabis-induced psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 86 | Neurotox Res 2007 Jan 11: 73-83 |
| PMID | 17449450 |
| Title | Are some genetic risk factors common to schizophrenia, bipolar disorder and depression? Evidence from DISC1, GRIK4 and NRG1. |
| Abstract | Depression is common in patients with schizophrenia and it is well established from family studies that rates of depression are increased among relatives of probands with schizophrenia, making it likely that the phenotypes described under the categories of affective and non-affective psychoses share some genetic risk factors. Family linkage studies have identified several chromosomal regions likely to contain risk genes for schizophrenia and bipolar disorder, suggesting common susceptibility loci. Candidate gene association studies have provided further evidence to suggest that some genes including two of the most studied candidates, Disrupted in schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) may be involved in both types of psychosis. We have recently identified another strong candidate for a role in both schizophrenia and affective disorders, GRIK4 a glutamate receptor mapped to chromosome 11q23 [Glutamate Receptor, Ionotropic, Kainate, type 4]. This gene is disrupted by a translocation breakpoint in a patient with schizophrenia, and case control studies show significant association of GRIK4 with both schizophrenia and bipolar disorder. Identifying genes implicated in the psychoses may eventually provide the basis for classification based on biology rather than symptoms, and suggest novel treatment strategies for these complex brain disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 87 | Hum. Mol. Genet. 2007 Dec 16: 2921-32 |
| PMID | 17884806 |
| Title | Alpha7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in neuregulin 1. |
| Abstract | Studies in cell culture and in animals suggest that neuregulin 1 (NRG1), a probable schizophrenia susceptibility gene, regulates the expression of the alpha7 nicotinic acetylcholine receptors (nAChRs). We hypothesized that schizophrenia-associated allelic variations within the NRG1 gene, via their effects on NRG1 isoform expression, would be associated with alterations in nAChR alpha7 receptor levels. We examined the effects of four disease-associated single-nucleotide polymorphisms (SNPs) in the 5' region of the NRG1 gene on nAChR alpha7 mRNA transcript expression in both the dorsolateral prefrontal cortex (DLPFC) and hippocampus of normal controls and patients with schizophrenia using quantitative real-time PCR. NRG1 risk alleles at SNPs SNP8NRG221132 and rs6994992 predicted significantly lower nAChR alpha7 mRNA expression in the DLPFC. Haplotypes containing the risk alleles at the above SNPs were also associated with lower expression of nAChR alpha7 in the DLPFC. The genotype effect for rs6994992 and the haplotype effect were more pronounced within the schizophrenic patient group. To determine whether receptor levels follow that of mRNA expression, we performed receptor binding and autoradiography using [(125)I] alpha-bungarotoxin in the DLPFC. Consistent with the mRNA findings, we found a decrease in binding in risk allele carriers of SNP8NRG221132 as compared with heterozygous individuals. Together, these results suggest that the molecular mechanism of the association between NRG1 risk alleles and schizophrenia may include down-regulation of nAChR alpha7 expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 88 | Proc. Biol. Sci. 2007 Nov 274: 2801-10 |
| PMID | 17785269 |
| Title | Adaptive evolution of genes underlying schizophrenia. |
| Abstract | schizophrenia poses an evolutionary-genetic paradox because it exhibits strongly negative fitness effects and high heritability, yet it persists at a prevalence of approximately 1% across all human cultures. Recent theory has proposed a resolution: that genetic liability to schizophrenia has evolved as a secondary consequence of selection for human cognitive traits. This hypothesis predicts that genes increasing the risk of this disorder have been subject to positive selection in the evolutionary history of humans and other primates. We evaluated this prediction using tests for recent selective sweeps in human populations and maximum-likelihood tests for selection during primate evolution. Significant evidence for positive selection was evident using one or both methods for 28 of 76 genes demonstrated to mediate liability to schizophrenia, including DISC1, DTNBP1 and NRG1, which exhibit especially strong and well-replicated functional and genetic links to this disorder. Strong evidence of non-neutral, accelerated evolution was found for DISC1, particularly for exon 2, the only coding region within the schizophrenia-associated haplotype. Additionally, genes associated with schizophrenia exhibited a statistically significant enrichment in their signals of positive selection in HapMap and PAML analyses of evolution along the human lineage, when compared with a control set of genes involved in neuronal activities. The selective forces underlying adaptive evolution of these genes remain largely unknown, but these findings provide convergent evidence consistent with the hypothesis that schizophrenia represents, in part, a maladaptive by-product of adaptive changes during human evolution. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 89 | Schizophr Bull 2007 Jul 33: 905-11 |
| PMID | 17551090 |
| Title | The genetic deconstruction of psychosis. |
| Abstract | Psychiatric research, including the search for predisposing genes, has tended to proceed under the assumptions that schizophrenia and bipolar disorder, as defined in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and International Statistical Classification of Diseases, 10th Revision, are discrete disease entities with distinct etiology and pathogenesis and that these disease entities can be identified by current "operational" diagnostic conventions. However, recent findings emerging from genetic studies show increasing evidence for an overlap in genetic susceptibility across the traditional binary classification of psychosis. Moreover, the emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, variation in Disrupted in schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) may confer susceptibility to a form of illness with mixed features of schizophrenia and mania. The elucidation of genotype-phenotype relationships is at an early stage, but current findings highlight the need to consider alternative approaches to classification and conceptualization for psychiatric research rather than continuing to rely heavily on the traditional categorical approach. We can expect that, over the coming years, molecular genetics will catalyze a reappraisal of psychiatric nosology as well as contribute in a major way to our understanding of pathophysiology and to the development of improved treatments. However, our understanding of the brain mechanisms that link specific gene actions and products to the subjective experience of psychopathological symptoms is likely to be bridged by employing intermediate (or endo-) phenotypes in the domains such as cognition, neurophysiology, or neuroanatomy rather than relying upon clinical measures alone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 90 | Neuroscience 2007 Jun 147: 18-27 |
| PMID | 17512671 |
| Title | Phenotypic characterization of spatial cognition and social behavior in mice with 'knockout' of the schizophrenia risk gene neuregulin 1. |
| Abstract | Neuregulin-1 (NRG1) has been identified as a candidate susceptibility gene for schizophrenia. In the present study the functional role of the NRG1 gene, as it relates to cognitive and social processes known to be disrupted in schizophrenia, was assessed in mice with heterozygous deletion of transmembrane (TM)-domain NRG1 in comparison with wildtypes (WT). Social affiliative behavior was assessed using the sociability and preference for social novelty paradigm, in terms of time spent in: (i) a chamber containing an unfamiliar conspecific vs. an empty chamber (sociability), or (ii) a chamber containing an unfamiliar conspecific vs. a chamber containing a familiar conspecific (preference for social novelty). Social dominance and aggressive behavior were examined in the resident-intruder paradigm. Spatial learning and memory were assessed using the Barnes maze paradigm, while spatial working memory was measured using the continuous variant of the spontaneous alternation task. Barnes maze data revealed intact spatial learning in NRG1 mutants, with elevated baseline latency to enter the escape hole in male NRG1 mutants reflecting an increase in activity level. Similarly, although a greater number of overall arm entries were found, spontaneous alternation was unaffected in NRG1 mice. Social affiliation data revealed NRG1 mutants to evidence a specific loss of WT preference for spending time with an unfamiliar as opposed to a familiar conspecific. This suggests that NRG1 mutants show a selective impairment in response to social novelty. While spatial learning and working memory processes appear intact, heterozygous deletion of TM-domain NRG1 was associated with disruption to social novelty behavior. These data inform at a novel phenotypic level on the functional role of this gene in the context of its association with risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 91 | Mol. Psychiatry 2007 Jul 12: 620-9 |
| PMID | 17440437 |
| Title | New genes associated with schizophrenia in neurite formation: a review of cell culture experiments. |
| Abstract | New genes consistently associated with schizophrenia include NRG1, Akt, DISC-1 and dysbindin-1. Since these genes participate in neurotransmission, neuroplasticity and neurodevelopment it has not been easy to elucidate which of these roles are abnormal in patients with schizophrenia. Neurite formation is identified as a crucial stage in development, and it is proposed that a defect in neurite formation originating from abnormally encoded proteins by these new genes could be at least an in vitro marker that reflects the most consistent molecular and neuroanatomical findings in schizophrenia. A systematic review of the literature linking the process of neurite formation to genes with replicated evidence that supported their association with schizophrenia was conducted. In addition, an outline of the process of neurite formation was included. Neurite formation was shown to be induced by neuregulins, the product of the gene NRG1. The activation of Akt, a serine/threonine kinase, promoted neurite formation in six independent studies. Conversely, two studies found that Akt inhibits neurite outgrowth. Stronger evidence supporting an association with the new genes related to schizophrenia and neurite formation comes from DISC-1. Defects in DISC-1 protein were shown to directly alter the process of neurite formation. Dysbindin-1 has not yet been directly implicated in neurite outgrowth. These findings suggest that the proteins encoded by NRG1, Akt and DISC-1 are implicated in the process of neurite formation in cellular models as well as, at least in part, animal models during development. Abnormalities in this process could have potential etiologic implications for schizophrenia. Direct evidence, however, of abnormal neurite formation in patients with schizophrenia is still missing. Limitations to this model are identified. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 92 | Genes Brain Behav. 2007 Mar 6: 113-9 |
| PMID | 17410640 |
| Title | The PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophrenia. |
| Abstract | Several putative schizophrenia susceptibility genes have recently been reported, but it is not clear whether these genes are associated with schizophrenia in general or with specific disease subtypes. In a previous study, we found an association of the neuregulin 1 (NRG1) gene with non-deficit schizophrenia only. We now report an association study of four schizophrenia candidate genes in patients with and without deficit schizophrenia, which is characterized by severe and enduring negative symptoms. Single-nucleotide polymorphisms (SNPs) were genotyped in the DTNBP1 (dysbindin), G72/G30 and RGS4 genes, and the relatively unknown PIP5K2A gene, which is located in a region of linkage with both schizophrenia and bipolar disorder. The sample consisted of 273 Dutch schizophrenia patients, 146 of whom were diagnosed with deficit schizophrenia and 580 controls. The strongest evidence for association was found for the A-allele of SNP rs10828317 in the PIP5K2A gene, which was associated with both clinical subtypes (P = 0.0004 in the entire group; non-deficit P = 0.016, deficit P = 0.002). Interestingly, this SNP leads to a change in protein composition. In RGS4, the G-allele of the previously reported SNP RGS4-1 (single and as part of haplotypes with SNP RGS4-18) was associated with non-deficit schizophrenia (P = 0.03) but not with deficit schizophrenia (P = 0.79). SNPs in the DTNBP1 and G72/G30 genes were not significantly associated in any group. In conclusion, our data provide further evidence that specific genes may be involved in different schizophrenia subtypes and suggest that the PIP5K2A gene deserves further study as a general susceptibility gene for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 93 | Biol. Psychiatry 2007 Oct 62: 784-92 |
| PMID | 17336946 |
| Title | Impact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level. |
| Abstract | Aspects of cognitive function and schizotypy have been proposed as potential endophenotypes for schizophrenia. It is unknown whether the expression of these endophenotypes at the population level is modulated by the genetic variability of candidate susceptibility genes for schizophrenia. We examined the potential impact of 18 single nucleotide polymorphisms (SNPs) within the DTNBP1, NRG1, DAOA/G32, and DAAO genes, on cognition and self-rated schizotypy, in a representative population of 2243 young male military conscripts. Single SNP and haplotype associations were evaluated. The DTNBP1 SNPs rs2619522 and rs760761 exhibited several single marker associations, the minor alleles being associated with lower attention capacity but also a decrease in positive and paranoid schizotypy scores. The DTNBP1 haplotype load had borderline associations with nonverbal IQ, paranoid schizotypy, and sustained attention. For individual NRG1 polymorphisms, isolated but weak signals of association were noted with sustained attention and working memory but not schizotypy. The risk allele of functional SNP8NRG243177 was associated with reduced spatial working memory capacity. An isolated effect of DAAO haplotype variability was noted on negative and disorganization schizotypy. No convincing association of DAOA/G32 variability was detected. The DTNBP1 and, less so, NRG1 and DAAO variants might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 94 | Psychopharmacology (Berl.) 2007 Jun 192: 325-36 |
| PMID | 17333138 |
| Title | Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Delta9-tetrahydrocannabinol. |
| Abstract | Cannabis use may precipitate schizophrenia especially if the individual has a genetic vulnerability to this mental disorder. Human and animal research indicates that neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. The aim of this study was to investigate whether dysfunction in the NRG1 gene modulates the behavioural effects of Delta(9)-tetrahydrocannabinol (THC), the major psychotropic component of cannabis. Heterozygous NRG1 transmembrane-domain knockout mice (NRG1 HET) were treated with acute THC (0, 5 or 10 mg/kg i.p.) 30 min before being tested using open field (OF), hole board (HB), light-dark (LD), elevated plus maze (EPM), social interaction (SI) and prepulse inhibition (PPI) tests. NRG1 HET mice showed differences in baseline behaviour with regard to locomotor activity, exploration and anxiety. More importantly, they were more sensitive to the locomotor suppressant actions of THC compared to wild type-like (WT) mice. In addition, NRG1 HET mice expressed a greater THC-induced enhancement in % PPI than WT mice. The effects of THC on anxiety-related behaviour were task-dependent, with NRG1 HET mice being more susceptible than WT mice to the anxiogenic effects of THC in LD, but not in the EPM, SI and OF tests. NRG1 HET mice were more sensitive to the acute effects of THC in an array of different behaviours including those that model symptoms of schizophrenia. It appears that variation in the schizophrenia-related neuregulin 1 gene alters the sensitivity to the behavioural effects of cannabinoids. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 95 | Genes Brain Behav. 2007 Oct 6: 677-87 |
| PMID | 17309661 |
| Title | Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia. |
| Abstract | Human genetic studies have shown that neuregulin 1 (NRG1) is a potential susceptibility gene for schizophrenia. NRG1 influences various neurodevelopmental processes, which are potentially related to schizophrenia. The neurodevelopmental theory of schizophrenia suggests that interactions between genetic and environmental factors are responsible for biochemical alterations leading to schizophrenia. To investigate these interactions and to match experimental design with the pathophysiology of schizophrenia, we applied a comprehensive behavioural phenotyping strategy for motor activity, exploration and anxiety in a heterozygous NRG1 transmembrane domain mutant mouse model (NRG1 HET) using different housing conditions and age groups. We observed a locomotion- and exploration-related hyperactive phenotype in NRG1 HETs. Increased age had a locomotion- and exploration-inhibiting effect, which was significantly attenuated in mutant mice. Environmental enrichment (EE) had a stimulating influence on locomotion and exploration. The impact of EE was more pronounced in NRG1 hypomorphs. Our study also showed a moderate task-specific anxiolytic-like phenotype for NRG1 HETs, which was influenced by external factors. The behavioural phenotype detected in heterozygous NRG1 mutant mice is not specific to schizophrenia per se, but the increased sensitivity of mutant mice to exogenous factors is consistent with the pathophysiology of schizophrenia and the neurodevelopmental theory. Our findings reinforce the importance of carefully controlling experimental designs for external factors and of comprehensive, integrative phenotyping strategies. Thus, NRG1 HETs may, in combination with other genetic and drug models, help to clarify pathophysiological mechanisms behind schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 96 | Mol. Psychiatry 2007 Jan 12: 94-104 |
| PMID | 16940976 |
| Title | Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population. |
| Abstract | Neuregulin 1 (NRG1) is a strong candidate for involvement in the aetiology of schizophrenia. A haplotype, initially identified as showing association in the Icelandic and Scottish populations, has shown a consistent effect size in multiple European populations. Additionally, NRG1 has been implicated in susceptibility to bipolar disorder. In this first study to select markers systematically on the basis of linkage disequilibrium across the entire NRG1 gene, we used haplotype-tagging single-nucleotide polymorphisms to identify single markers and haplotypes associated with schizophrenia and bipolar disorder in an independently ascertained Scottish population. Haplotypes in two regions met an experiment-wide significance threshold of P=0.0016 (Nyholt's SpD) and were permuted to correct for multiple testing. Region A overlaps with the Icelandic haplotype and shows nominal association with schizophrenia (P=0.00032), bipolar disorder (P=0.0011), and the combined case group (P=0.0017). This region includes the 5' exon of the NRG1 GGF2 isoform and overlaps the expressed sequence tag (EST) cluster Hs.97362. However, no haplotype in Region A remains significant after permutation analysis (P>0.05). Region B contains a haplotype associated with both schizophrenia (P=0.00014), and the combined case group (P=0.000062), although it does not meet Nyholt's threshold in bipolar disorder alone (P=0.0022). This haplotype remained significant after permutation analysis in both the schizophrenia and combined case groups (P=0.024 and P=0.016, respectively). It spans a approximately 136 kb region that includes the coding sequence of the sensory and motor neuron derived factor (SMDF) isoform and 3' exons of all other known NRG1 isoforms. Our study identifies a new of NRG1 region involved in schizophrenia and bipolar disorder in the Scottish population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 97 | Cell. Physiol. Biochem. 2007 -1 20: 687-702 |
| PMID | 17982252 |
| Title | Molecular mechanisms of schizophrenia. |
| Abstract | schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 98 | Hum. Mol. Genet. 2007 Dec 16: 2921-32 |
| PMID | 17884806 |
| Title | Alpha7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in neuregulin 1. |
| Abstract | Studies in cell culture and in animals suggest that neuregulin 1 (NRG1), a probable schizophrenia susceptibility gene, regulates the expression of the alpha7 nicotinic acetylcholine receptors (nAChRs). We hypothesized that schizophrenia-associated allelic variations within the NRG1 gene, via their effects on NRG1 isoform expression, would be associated with alterations in nAChR alpha7 receptor levels. We examined the effects of four disease-associated single-nucleotide polymorphisms (SNPs) in the 5' region of the NRG1 gene on nAChR alpha7 mRNA transcript expression in both the dorsolateral prefrontal cortex (DLPFC) and hippocampus of normal controls and patients with schizophrenia using quantitative real-time PCR. NRG1 risk alleles at SNPs SNP8NRG221132 and rs6994992 predicted significantly lower nAChR alpha7 mRNA expression in the DLPFC. Haplotypes containing the risk alleles at the above SNPs were also associated with lower expression of nAChR alpha7 in the DLPFC. The genotype effect for rs6994992 and the haplotype effect were more pronounced within the schizophrenic patient group. To determine whether receptor levels follow that of mRNA expression, we performed receptor binding and autoradiography using [(125)I] alpha-bungarotoxin in the DLPFC. Consistent with the mRNA findings, we found a decrease in binding in risk allele carriers of SNP8NRG221132 as compared with heterozygous individuals. Together, these results suggest that the molecular mechanism of the association between NRG1 risk alleles and schizophrenia may include down-regulation of nAChR alpha7 expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 99 | Biol. Psychiatry 2007 Oct 62: 784-92 |
| PMID | 17336946 |
| Title | Impact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level. |
| Abstract | Aspects of cognitive function and schizotypy have been proposed as potential endophenotypes for schizophrenia. It is unknown whether the expression of these endophenotypes at the population level is modulated by the genetic variability of candidate susceptibility genes for schizophrenia. We examined the potential impact of 18 single nucleotide polymorphisms (SNPs) within the DTNBP1, NRG1, DAOA/G32, and DAAO genes, on cognition and self-rated schizotypy, in a representative population of 2243 young male military conscripts. Single SNP and haplotype associations were evaluated. The DTNBP1 SNPs rs2619522 and rs760761 exhibited several single marker associations, the minor alleles being associated with lower attention capacity but also a decrease in positive and paranoid schizotypy scores. The DTNBP1 haplotype load had borderline associations with nonverbal IQ, paranoid schizotypy, and sustained attention. For individual NRG1 polymorphisms, isolated but weak signals of association were noted with sustained attention and working memory but not schizotypy. The risk allele of functional SNP8NRG243177 was associated with reduced spatial working memory capacity. An isolated effect of DAAO haplotype variability was noted on negative and disorganization schizotypy. No convincing association of DAOA/G32 variability was detected. The DTNBP1 and, less so, NRG1 and DAAO variants might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 100 | Mol. Psychiatry 2008 Sep 13: 873-7 |
| PMID | 18195713 |
| Title | Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. |
| Abstract | The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-alpha) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 101 | Behav. Neurosci. 2008 Aug 122: 748-59 |
| PMID | 18729627 |
| Title | Behavioral profile of a heterozygous mutant mouse model for EGF-like domain neuregulin 1. |
| Abstract | Human genetic studies have demonstrated that the neuregulin 1 gene (NRG1) is involved in the development of schizophrenia. Alternative splicing of NRG1 results in at least 15 distinct isoforms and all contain an extracellular epidermal growth factor (EGF)-like domain, which is sufficient for NRG1's biological activity. Here, we characterize a heterozygous mutant model for mouse EGF-like domain neuregulin 1 (NRG1) regarding schizophrenia-related behavioral domains. A comprehensive, multitiered phenotyping strategy was used to investigate locomotion, exploration, anxiety-related behaviors, and sensorimotor gating. NRG1 mutant mice exhibited a hyper-locomotive phenotype and an improved ability to habituate to a new environment. Extensive analysis of anxiety-related behaviors revealed a wild type-like phenotype in this domain. However, a moderate impairment in sensorimotor gating was found after pharmacological challenge using psychoactive substances. Our study adds to the increasing behavioral data available from a variety of animal models for NRG1 isoforms. We suggest a standardized and comprehensive behavioral phenotyping approach to distinguish between the different models and to clarify their relevance for schizophrenia research. Future behavioral investigations will focus on the negative and cognitive symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 102 | Int. J. Neuropsychopharmacol. 2008 Jun 11: 553-61 |
| PMID | 18184445 |
| Title | Chronic antipsychotic drug administration alters the expression of neuregulin 1beta, ErbB2, ErbB3, and ErbB4 in the rat prefrontal cortex and hippocampus. |
| Abstract | Neuregulin 1 (NRG1) has been identified as a susceptibility gene for schizophrenia, and dysregulation of NRG1 and its ErbB receptors is implicated in the pathophysiology of the disorder. The present study examined the protein expression levels of NRG1beta, ErbB2, ErbB3 and ErbB4 in the rat prefrontal cortex and hippocampus following a 4-wk administration of haloperidol (1 mg/kg i.p.), clozapine (10 mg/kg i.p.), or risperidone (1 mg/kg i.p.) by using immunohistochemistry and Western blot. The results showed that haloperidol promoted the expression of NRG1beta and ErbB4, whereas clozapine inhibited NRG1beta expression in the rat prefrontal cortex. Both haloperidol and clozapine significantly increased the protein levels of NRG1beta and ErbB receptors in the rat hippocampus. Repeated administration of risperidone only increased the expression of NRG1beta and ErbB4 in the hippocampus. Our findings demonstrate that antipsychotic drugs differentially regulate the expression of NRG1 and ErbB receptors in the rat brain, which may provide insight into the molecular basis of the pharmacological profile of antipsychotic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 103 | Nat. Rev. Neurosci. 2008 Jun 9: 437-52 |
| PMID | 18478032 |
| Title | Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. |
| Abstract | schizophrenia is a highly debilitating mental disorder that affects approximately 1% of the general population, yet it continues to be poorly understood. Recent studies have identified variations in several genes that are associated with this disorder in diverse populations, including those that encode neuregulin 1 (NRG1) and its receptor ErbB4. The past few years have witnessed exciting progress in our knowledge of NRG1 and ErbB4 functions and the biological basis of the increased risk for schizophrenia that is potentially conferred by polymorphisms in the two genes. An improved understanding of the mechanisms by which altered function of NRG1 and ErbB4 contributes to schizophrenia might eventually lead to the development of more effective therapeutics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 104 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Oct 147B: 1013-8 |
| PMID | 18186075 |
| Title | No association between the protein tyrosine phosphatase, receptor-type, Z Polypeptide 1 (PTPRZ1) gene and schizophrenia in the Japanese population. |
| Abstract | NRG1-ERBB signaling influences the risk for schizophrenia pathology. A recent study has reported that MAGI1, MAGI2, and protein tyrosine phosphatase, receptor-type, Z polypeptide 1 (PTPRZ1; located on 7q31.3) gene products regulate the NRG1-ERBB4 signaling pathway, and PTPRZ1 is associated with schizophrenia in a Caucasian population. By applying a gene-based association concept, we analyzed any association between PTPRZ1 tagging SNPs and schizophrenia in the Japanese population (576 schizophrenics and 768 controls). After linkage disequilibrium analysis, 29 single nucleotide polymorphisms (SNPs) were genotyped using a 5'-exonuclease allelic discrimination assay. We found a significant association of one tagging SNP in a genotype-wise analysis (P = 0.007); however, this might be resulted from type I error due to multiple testing (P = 0.17 after SNPSpD correction). No association was observed between schizophrenic patients and controls in either allelic, genotypic, or haplotypic analyses. Our results therefore suggest that PTPRZ1 is unlikely to be related to the development of schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 105 | J. Neurosci. 2008 Sep 28: 9111-6 |
| PMID | 18784291 |
| Title | Presynaptic type III neuregulin 1 is required for sustained enhancement of hippocampal transmission by nicotine and for axonal targeting of alpha7 nicotinic acetylcholine receptors. |
| Abstract | Both the neuregulin 1 (NRG1) and alpha7 nicotinic acetylcholine receptor (alpha7*nAChRs) genes have been linked to schizophrenia and associated sensory-motor gating deficits. The prominence of nicotine addiction in schizophrenic patients is reflected in the normalization of gating deficits by nicotine self-administration. To assess the role of presynaptic type III NRG1 at hippocampal-accumbens synapses, an important relay in sensory-motor gating, we developed a specialized preparation of chimeric circuits in vitro. Synaptic relays from NRG1(tm1Lwr) heterozygote ventral hippocampal slices to wild-type (WT) nucleus accumbens neurons (1) lack a sustained, alpha7*nAChRs-mediated phase of synaptic potentiation seen in comparable WT/WT circuits and (2) are deficient in targeting alpha7*nAChRs to presynaptic sites. Thus, selective alteration of the level of presynaptic type III NRG1 dramatically affects the modulation of glutamatergic transmission at ventral hippocampal to nucleus accumbens synapses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 106 | Proc. Natl. Acad. Sci. U.S.A. 2008 Jul 105: 9775-80 |
| PMID | 18626010 |
| Title | Deficiency of Aph1B/C-gamma-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment. |
| Abstract | Regulated intramembrane proteolysis by gamma-secretase cleaves proteins in their transmembrane domain and is involved in important signaling pathways. At least four different gamma-secretase complexes have been identified, but little is known about their biological role and specificity. Previous work has demonstrated the involvement of the Aph1A-gamma-secretase complex in Notch signaling, but no specific function could be assigned to Aph1B/C-gamma-secretase. We demonstrate here that the Aph1B/C-gamma-secretase complex is expressed in brain areas relevant to schizophrenia pathogenesis and that Aph1B/C deficiency causes pharmacological and behavioral abnormalities that can be reversed by antipsychotic drugs. At the molecular level we find accumulation of NRG1 fragments in the brain of Aph1BC(-/-) mice. Our observations gain clinical relevance by the demonstration that a Val-to-Leu mutation in the NRG1 transmembrane domain, associated with increased risk for schizophrenia, affects gamma-secretase cleavage of NRG1. This finding suggests that dysregulation of intramembrane proteolysis of NRG1 could increase risk for schizophrenia and related disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 107 | Z Kinder Jugendpsychiatr Psychother 2008 Jan 36: 17-26 |
| PMID | 18476600 |
| Title | [Genetic findings in schizophrenia]. |
| Abstract | schizophrenia is characterized by a great heterogeneity of symptoms and functional deficits, especially of cognition. Different phenotypes are thought to result from the interaction of genetic predisposition and environmental factors. Pathophysiological models range from the dopamine and glutamate hypotheses to the hypothesis of free radicals and the hypotheses of neurodevelopment as opposed to neurodegeneration. In addition to the neurobiological approaches, linkage studies and subsequent finemappings deliver evidence with regard to genes potentially involved in schizophrenia. The most important candidate genes, such as dysbindin (DTNBP1), neuregulin (NRG1) and DISC-1 (disrupted-in schizophrenia-1), are thought to influence neurotransmission, as well as the development and maintenance of the structure of neuronal networks. The list of potential candidates includes numerous other genes as well. In conclusion, multiple genetic, neurobiological, and exogenous factors are assumed to interact in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 108 | Eur. Psychiatry 2008 Aug 23: 344-9 |
| PMID | 18455369 |
| Title | Genetic variation in the schizophrenia-risk gene neuregulin1 correlates with personality traits in healthy individuals. |
| Abstract | Differences in personality traits have long been acknowledged as potential risk factors in developing psychiatric disorders. Lately, several susceptibility genes of different psychiatric disorders have been linked to personality traits. This has not been done for schizophrenia yet. Neuregulin1 has been repeatedly shown to be associated with schizophrenia and is involved in numerous neurodevelopmental functions such as neuronal migration and myelination. The impact of this gene might also modulate personality traits in healthy subjects. The NRG1 status of 523 healthy subjects was determined with a single nucleotide polymorphism (SNP8NRG221533) which has been described as a tagging marker being part of the core at-risk haplotype for schizophrenia. Genotype was correlated with personality traits using the NEO-FFI questionnaire. Subjects with the NRG1 risk allele scored higher on neuroticism (p<.05) and lower on conscientiousness (p<.05). Further, interactions of genotype by gender for extraversion (p<.05), openness (p<.05) and conscientiousness (p<.05) were found with men carrying the risk allele scoring the lowest. The data indicate that the NRG1 gene which has found to be associated with schizophrenia may also influence personality differences in healthy subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 109 | J Psychiatr Res 2008 Nov 43: 1-6 |
| PMID | 18291420 |
| Title | Neuregulin-1 haplotype HAP(ICE) is associated with lower hippocampal volumes in schizophrenic patients and in non-affected family members. |
| Abstract | The neuregulin-1 (NRG1) gene on chromosome 8p has been suggested as a potential susceptibility gene for schizophrenia. The exact way in which genetic variation in NRG1 might impact on this susceptibility for the disorder is a focus of current research. The present study aimed at investigating the possible relationship between a putative NRG1 at-risk haplotype (HAP(ICE)) and hippocampal volumes in schizophrenic patients and their healthy first-degree relatives. We genotyped 30 schizophrenic patients and 52 non-affected family members with regard to the presence or absence of the NRG1 haplotype HAP(ICE). Structural magnetic resonance imaging was used to determine hippocampal brain volumes in the same subjects. Patients and relatives carrying haplotype HAP(ICE) both had smaller relative hippocampal volumes as compared to patients or relatives who did not carry this haplotype. These findings provide first direct evidence for a link between NRG1 genetic variation and hippocampal volume reductions in schizophrenic patients and non-affected relatives. This preliminary evidence may help to guide further research into the pathophysiological pathways that underlie this genetic susceptibility for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 110 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 606-11 |
| PMID | 18163393 |
| Title | Gene copy number variation in schizophrenia. |
| Abstract | Recent reports have highlighted the possibility that gene copy number variations play a role in the development of complex disorders and have suggested that some variations are very common in schizophrenic patients. We have carried out a comparative genomic hybridization screen using oligonucleotide probes of 891 candidate genes to look for very common copy number variance in schizophrenic patients. In addition we have developed a new approach for the detection and validation of putative copy number variation based upon established methods of allele quantification by DNA pooling and have used it to study 15 major candidates including dysbindin (DTNBP1), neuregulin (NRG1), RGS4 and DISC1. With the exception of positive control sequences, no copy number variations were found for any of the genes in any samples by the use of either technique. Our data for the genes studied are in line with the known existence and frequency of CNVs as reported by recent large scale studies and suggest that gene copy number variations are not more common in schizophrenics than controls, although large ethnic differences cannot be excluded. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 111 | Schizophr. Res. 2008 Feb 99: 341-9 |
| PMID | 18054201 |
| Title | Increased levels of serotonin 2A receptors and serotonin transporter in the CNS of neuregulin 1 hypomorphic/mutant mice. |
| Abstract | Changes in neuregulin 1 expression have been reported in the CNS from subjects with schizophrenia. As neuregulin 1 is important in cortical development we postulated that changes in neuregulin 1 expression may contribute towards changes in cholinergic, glutamatergic and serotonergic markers that are well documented in the CNS of subjects with that disorder. To begin to test this hypothesis, we used in situ radioligand binding to measure levels of muscarinic M1/M4 receptors, the kainate receptor, the NMDA receptor, the serotonin 2A receptor, the serotonin 1A receptor and the serotonin transporter in the CNS from heterozygous transmembrane domain neuregulin 1 mutant mice. The major outcomes from these studies was the demonstration of an overall increase in levels of the serotonin 2A receptor (F=11.3, d.f.=3,1,72, p=0.0012) and serotonin transporter (F=5.00, d.f.=1,3,72, p<0.05) in the mutant mice. Levels of the other receptors did not vary in the mutant mice compared to their wild type-like litter mates. These data are the first evidence to suggest that NRG1 gene expression may be involved in regulating the development of the serotonergic system in the mammalian CNS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 112 | Schizophr Bull 2008 Jan 34: 9-12 |
| PMID | 18032396 |
| Title | Neuregulin 1 genotype and schizophrenia. |
| Abstract | The neuregulin 1 (NRG1) gene has been the subject of considerable excitement within the psychiatric genetics literature since it was originally identified as a potential susceptibility locus for schizophrenia. Here we provide an update of our first meta-analysis of this association. Case-control and family-based genetic association studies of the NRG1 gene in healthy control groups and clinically diagnosed schizophrenia patients were included. We repeated the search strategy in our earlier meta-analysis for studies published between December 31, 2005, and September 30, 2007, and updated the results of our original meta-analysis accordingly. Superficially, the results of our updated meta-analysis are consistent with those in our previous report, although it is notable that the strength of evidence as based on our haplotype analysis has weakened over this period. The evidence for association of the SNP8NRG221533 polymorphism continued to be nonsignificant. We discuss a number of problems in the interpretation of a disparate and inconsistent gene-disease association literature, including the difficulties associated with determining what constitutes replication across studies which vary in their methods, marker sets employed, phenotype definition, and other study characteristics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 113 | Mol. Psychiatry 2008 Nov 13: 1054-9 |
| PMID | 17925794 |
| Title | The effects of a neuregulin 1 variant on white matter density and integrity. |
| Abstract | Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T(1)-weighted MRI) and integrity (DTI) was ascertained. Subjects with the risk-associated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 114 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Oct 147B: 1013-8 |
| PMID | 18186075 |
| Title | No association between the protein tyrosine phosphatase, receptor-type, Z Polypeptide 1 (PTPRZ1) gene and schizophrenia in the Japanese population. |
| Abstract | NRG1-ERBB signaling influences the risk for schizophrenia pathology. A recent study has reported that MAGI1, MAGI2, and protein tyrosine phosphatase, receptor-type, Z polypeptide 1 (PTPRZ1; located on 7q31.3) gene products regulate the NRG1-ERBB4 signaling pathway, and PTPRZ1 is associated with schizophrenia in a Caucasian population. By applying a gene-based association concept, we analyzed any association between PTPRZ1 tagging SNPs and schizophrenia in the Japanese population (576 schizophrenics and 768 controls). After linkage disequilibrium analysis, 29 single nucleotide polymorphisms (SNPs) were genotyped using a 5'-exonuclease allelic discrimination assay. We found a significant association of one tagging SNP in a genotype-wise analysis (P = 0.007); however, this might be resulted from type I error due to multiple testing (P = 0.17 after SNPSpD correction). No association was observed between schizophrenic patients and controls in either allelic, genotypic, or haplotypic analyses. Our results therefore suggest that PTPRZ1 is unlikely to be related to the development of schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 115 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Oct 147B: 1013-8 |
| PMID | 18186075 |
| Title | No association between the protein tyrosine phosphatase, receptor-type, Z Polypeptide 1 (PTPRZ1) gene and schizophrenia in the Japanese population. |
| Abstract | NRG1-ERBB signaling influences the risk for schizophrenia pathology. A recent study has reported that MAGI1, MAGI2, and protein tyrosine phosphatase, receptor-type, Z polypeptide 1 (PTPRZ1; located on 7q31.3) gene products regulate the NRG1-ERBB4 signaling pathway, and PTPRZ1 is associated with schizophrenia in a Caucasian population. By applying a gene-based association concept, we analyzed any association between PTPRZ1 tagging SNPs and schizophrenia in the Japanese population (576 schizophrenics and 768 controls). After linkage disequilibrium analysis, 29 single nucleotide polymorphisms (SNPs) were genotyped using a 5'-exonuclease allelic discrimination assay. We found a significant association of one tagging SNP in a genotype-wise analysis (P = 0.007); however, this might be resulted from type I error due to multiple testing (P = 0.17 after SNPSpD correction). No association was observed between schizophrenic patients and controls in either allelic, genotypic, or haplotypic analyses. Our results therefore suggest that PTPRZ1 is unlikely to be related to the development of schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 116 | J. Neurosci. 2008 Sep 28: 9111-6 |
| PMID | 18784291 |
| Title | Presynaptic type III neuregulin 1 is required for sustained enhancement of hippocampal transmission by nicotine and for axonal targeting of alpha7 nicotinic acetylcholine receptors. |
| Abstract | Both the neuregulin 1 (NRG1) and alpha7 nicotinic acetylcholine receptor (alpha7*nAChRs) genes have been linked to schizophrenia and associated sensory-motor gating deficits. The prominence of nicotine addiction in schizophrenic patients is reflected in the normalization of gating deficits by nicotine self-administration. To assess the role of presynaptic type III NRG1 at hippocampal-accumbens synapses, an important relay in sensory-motor gating, we developed a specialized preparation of chimeric circuits in vitro. Synaptic relays from NRG1(tm1Lwr) heterozygote ventral hippocampal slices to wild-type (WT) nucleus accumbens neurons (1) lack a sustained, alpha7*nAChRs-mediated phase of synaptic potentiation seen in comparable WT/WT circuits and (2) are deficient in targeting alpha7*nAChRs to presynaptic sites. Thus, selective alteration of the level of presynaptic type III NRG1 dramatically affects the modulation of glutamatergic transmission at ventral hippocampal to nucleus accumbens synapses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 117 | J Psychiatr Res 2008 Nov 43: 1-6 |
| PMID | 18291420 |
| Title | Neuregulin-1 haplotype HAP(ICE) is associated with lower hippocampal volumes in schizophrenic patients and in non-affected family members. |
| Abstract | The neuregulin-1 (NRG1) gene on chromosome 8p has been suggested as a potential susceptibility gene for schizophrenia. The exact way in which genetic variation in NRG1 might impact on this susceptibility for the disorder is a focus of current research. The present study aimed at investigating the possible relationship between a putative NRG1 at-risk haplotype (HAP(ICE)) and hippocampal volumes in schizophrenic patients and their healthy first-degree relatives. We genotyped 30 schizophrenic patients and 52 non-affected family members with regard to the presence or absence of the NRG1 haplotype HAP(ICE). Structural magnetic resonance imaging was used to determine hippocampal brain volumes in the same subjects. Patients and relatives carrying haplotype HAP(ICE) both had smaller relative hippocampal volumes as compared to patients or relatives who did not carry this haplotype. These findings provide first direct evidence for a link between NRG1 genetic variation and hippocampal volume reductions in schizophrenic patients and non-affected relatives. This preliminary evidence may help to guide further research into the pathophysiological pathways that underlie this genetic susceptibility for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 118 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 606-11 |
| PMID | 18163393 |
| Title | Gene copy number variation in schizophrenia. |
| Abstract | Recent reports have highlighted the possibility that gene copy number variations play a role in the development of complex disorders and have suggested that some variations are very common in schizophrenic patients. We have carried out a comparative genomic hybridization screen using oligonucleotide probes of 891 candidate genes to look for very common copy number variance in schizophrenic patients. In addition we have developed a new approach for the detection and validation of putative copy number variation based upon established methods of allele quantification by DNA pooling and have used it to study 15 major candidates including dysbindin (DTNBP1), neuregulin (NRG1), RGS4 and DISC1. With the exception of positive control sequences, no copy number variations were found for any of the genes in any samples by the use of either technique. Our data for the genes studied are in line with the known existence and frequency of CNVs as reported by recent large scale studies and suggest that gene copy number variations are not more common in schizophrenics than controls, although large ethnic differences cannot be excluded. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 119 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 606-11 |
| PMID | 18163393 |
| Title | Gene copy number variation in schizophrenia. |
| Abstract | Recent reports have highlighted the possibility that gene copy number variations play a role in the development of complex disorders and have suggested that some variations are very common in schizophrenic patients. We have carried out a comparative genomic hybridization screen using oligonucleotide probes of 891 candidate genes to look for very common copy number variance in schizophrenic patients. In addition we have developed a new approach for the detection and validation of putative copy number variation based upon established methods of allele quantification by DNA pooling and have used it to study 15 major candidates including dysbindin (DTNBP1), neuregulin (NRG1), RGS4 and DISC1. With the exception of positive control sequences, no copy number variations were found for any of the genes in any samples by the use of either technique. Our data for the genes studied are in line with the known existence and frequency of CNVs as reported by recent large scale studies and suggest that gene copy number variations are not more common in schizophrenics than controls, although large ethnic differences cannot be excluded. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 120 | Eur Arch Psychiatry Clin Neurosci 2008 Jun 258 Suppl 2: 37-40 |
| PMID | 18516516 |
| Title | Common risk genes for affective and schizophrenic psychoses. |
| Abstract | The familial-genetic relationship between affective and schizophrenic disorders is receiving a re-emergence of interest. The reasons are a series of cross-diagnostic molecular-genetic discoveries: specific alleles in the genes for dysbindin (DTNBP1), neuregulin (NRG1) and DAOA (G72/G30) reveal associations for each of both groups of disorders in the same direction in some but not all reported studies. These findings cannot just be false positives because of confirming metaanalyses. Furthermore there is some pathophysiological support: the mentioned genes are involved in biochemical pathways, which are contributing to both disorders partly in a similar and partly in a different manner. The new levels of evidence enrich the classical continuity/discontinuity debate on the relationship between both groups of disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 121 | Biol. Psychiatry 2008 Sep 64: 438-42 |
| PMID | 18466879 |
| Title | Association of a nonsynonymous variant of DAOA with visuospatial ability in a bipolar family sample. |
| Abstract | Bipolar disorder and schizophrenia are hypothesized to share some genetic background. In a two-phase study, we evaluated the effect of five promising candidate genes for psychotic disorders, DAOA, COMT, DTNBP1, NRG1, and AKT1, on bipolar spectrum disorder, psychotic disorder, and related cognitive endophenotypes in a Finnish family-based sample ascertained for bipolar disorder. In initial screening of 362 individuals from 63 families, we found only marginal evidence for association with the diagnosis-based dichotomous classification. Those associations did not strengthen when we genotyped the complete sample of 723 individuals from 180 families. We observed a significant association of DAOA variants rs3916966 and rs2391191 with visuospatial ability (Quantitative Transmission Disequilibrium Test [QTDT]; p = 4 x 10(-6) and 5 x 10(-6), respectively) (n = 159) with the two variants in almost complete linkage disequilibrium. The COMT variant rs165599 also associated with visuospatial ability, and in our dataset, we saw an additive effect of DAOA and COMT variants on this neuropsychological trait. The ancestral allele (Arg) of the nonsynonymous common DAOA variant rs2391191 (Arg30Lys) was found to predispose to impaired performance. The DAOA gene may play a role in predisposing individuals to a mixed phenotype of psychosis and mania and to impairments in related neuropsychological traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 122 | Am J Psychiatry 2008 Apr 165: 497-506 |
| PMID | 18198266 |
| Title | No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. |
| Abstract | The authors carried out a genetic association study of 14 schizophrenia candidate genes (RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF). This study tested the hypothesis of association of schizophrenia with common single nucleotide polymorphisms (SNPs) in these genes using the largest sample to date that has been collected with uniform clinical methods and the most comprehensive set of SNPs in each gene. The sample included 1,870 cases (schizophrenia and schizoaffective disorder) and 2,002 screened comparison subjects (i.e. controls), all of European ancestry, with ancestral outliers excluded based on analysis of ancestry-informative markers. The authors genotyped 789 SNPs, including tags for most common SNPs in each gene, SNPs previously reported as associated, and SNPs located in functional domains of genes such as promoters, coding exons (including nonsynonymous SNPs), 3' untranslated regions, and conserved noncoding sequences. After extensive data cleaning, 648 SNPs were analyzed for association of single SNPs and of haplotypes. Neither experiment-wide nor gene-wide statistical significance was observed in the primary single-SNP analyses or in secondary analyses of haplotypes or of imputed genotypes for additional common HapMap SNPs. Results in SNPs previously reported as associated with schizophrenia were consistent with chance expectation, and four functional polymorphisms in COMT, DRD2, and HTR2A did not produce nominally significant evidence to support previous evidence for association. It is unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects cannot be ruled out. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 123 | Proc. Natl. Acad. Sci. U.S.A. 2008 Apr 105: 5585-90 |
| PMID | 18385378 |
| Title | Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. |
| Abstract | beta-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-beta precursor protein (APP) leading to the generation of amyloid-beta peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1(+/-) mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. To test this hypothesis, we analyze the behaviors considered to be rodent analogs of clinical features of schizophrenia in BACE1(-/-) mice with impaired processing of NRG1. We demonstrate that BACE1(-/-) mice exhibit deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with clozapine, an atypical antipsychotic drug. Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1(-/-) mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1(-/-) mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 124 | J. Neurosci. 2008 Jul 28: 6872-83 |
| PMID | 18596162 |
| Title | Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components. |
| Abstract | Neuregulin-1 (NRG1)/erbB signaling regulates neuronal development, migration, myelination, and synaptic maintenance. The NRG1 gene is a schizophrenia susceptibility gene. To understand the contribution of NRG1 signaling to adult brain structure and behaviors, we studied the regulation of type III NRG1 expression and evaluated the effect of decreased expression of the type III NRG1 isoforms. Type III NRG1 is transcribed by a promoter distinct from those for other NRG1 isoforms and, in the adult brain, is expressed in the medial prefrontal cortex, ventral hippocampus, and ventral subiculum, regions involved in the regulation of sensorimotor gating and short-term memory. Adult heterozygous mutant mice with a targeted disruption for type III NRG1 (NRG1(tm1.1Lwr+/-)) have enlarged lateral ventricles and decreased dendritic spine density on subicular pyramidal neurons. Magnetic resonance imaging of type III NRG1 heterozygous mice revealed hypofunction in the medial prefrontal cortex and the hippocampal CA1 and subiculum regions. Type III NRG1 heterozygous mice also have impaired performance on delayed alternation memory tasks, and deficits in prepulse inhibition (PPI). Chronic nicotine treatment eliminated differences in PPI between type III NRG1 heterozygous mice and their wild-type littermates. Our findings demonstrate a role of type III NRG1 signaling in the maintenance of corticostriatal components and in the neural circuits involved in sensorimotor gating and short-term memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 125 | Novartis Found. Symp. 2008 -1 289: 165-77; discussion 177-9, 193-5 |
| PMID | 18497102 |
| Title | Neuregulins and neuronal plasticity: possible relevance in schizophrenia. |
| Abstract | Polymorphisms in the Neuregulin 1 (NRG1) and ErbB4 receptor genes have been associated with schizophrenia in numerous cohort and family studies, and biochemical measurements from postmortem prefrontal cortex homogenates suggest that NRG/ErbB signalling is altered in schizophrenia. Moreover, recent work from our group, and from others, indicates that NRG/ErbB signalling has a role in regulating glutamatergic transmission--an intriguing finding given that glutamatergic hypofunction has been proposed to be involved in the pathogenesis underlying schizophrenia. Here we will provide a brief background of the complexity of the NRG/ErbB signalling system. We will then focus on how NRG1 reverses (depotentiates) long-term potentiation (LTP) at hippocampal Schaeffer collateral--CA1 glutamatergic synapses in the adult brain. Specifically, we found that NRG1 depotentiates LTP in an activity- and time-dependent manner. A role of endogenous NRG for regulating plasticity at hippocampal synapses is supported by experiments demonstrating that ErbB receptor antagonists completely block LTP depotentiation by brief theta-pulse stimuli, a subthreshold stimulus paradigm that reverses LTP in live animals. Preliminary results indicate that NRG1-mediated LTP depotentiation is NMDA receptor independent, and manifests as an internalization of GluR1-containing AMPA receptors. The importance of the NRG/ ErbB signalling pathway in regulating homeostasis at glutamatergic synapses, and its possible implications for schizophrenia, will be discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 126 | BMC Bioinformatics 2008 -1 9 Suppl 12: S23 |
| PMID | 19091023 |
| Title | A protein interaction based model for schizophrenia study. |
| Abstract | schizophrenia is a complex disease with multiple factors contributing to its pathogenesis. In addition to environmental factors, genetic factors may also increase susceptibility. In other words, schizophrenia is a highly heritable disease. Some candidate genes have been deduced on the basis of their known function with others found on the basis of chromosomal location. Individuals with multiple candidate genes may have increased risk. However it is not clear what kind of gene combinations may produce the disease phenotype. Their collective effect remains to be studied. Most pathways except metabolic pathways are rich in protein-protein interactions (PPIs). Thus, the PPI network contains pathway information, even though the upstream-downstream relation of PPI is yet to be explored. Here we have constructed a PPI sub-network by extracting the nearest neighbour of the 36 reported candidate genes described in the literature. Although these candidate genes were discovered by different approaches, most of the proteins formed a cluster. Two major protein interaction modules were identified on the basis of the pairwise distance among the proteins in this sub-network. The large and small clusters might play roles in synaptic transmission and signal transduction, respectively, based on gene ontology annotation. The protein interactions in the synaptic transmission cluster were used to explain the interaction between the NRG1 and CACNG2 genes, which was found by both linkage and association studies. This working hypothesis is supported by the co-expression analysis based on public microarray gene expression. On the basis of the protein interaction network, it appears that the NRG1-triggered NMDAR protein internalization and the CACNG2 mediated AMPA receptor recruiting may act together in the glutamatergic signalling process. Since both the NMDA and AMPA receptors are calcium channels, this process may regulate the influx of Ca2+. Reducing the cation influx might be one of the disease mechanisms for schizophrenia. This PPI network analysis approach combined with the support from co-expression analysis may provide an efficient way to propose pathogenetic mechanisms for various highly heritable diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 127 | Br. J. Pharmacol. 2008 Mar 153 Suppl 1: S120-4 |
| PMID | 18193072 |
| Title | Neuroimaging and molecular genetics of schizophrenia: pathophysiological advances and therapeutic potential. |
| Abstract | There is impressive evidence for the involvement of several genetic risk factors in the aetiopathogenesis of schizophrenia. Most of these genes impact on neuropharmacological systems. Examining their relationship with brain imaging indices is arguably the best currently available method of examining these effects in vivo. In a sample of young, initially healthy people at high genetic risk of schizophrenia brain structure was measured with structural magnetic resonance imaging (sMRI) and brain function was indexed with neuropsychological tests and functional MRI. Regular detailed clinical assessments established whether subjects had developed psychotic symptoms and/or schizophrenia itself. The Catechol-O-Methyl Transferase (COMT) Val allele increased the risk of schizophrenia in this cohort in a dose-dependent manner. Subjects with this allele had reduced grey matter density in anterior cingulate cortex and increased fMRI activation in lateral prefrontal cortex and anterior and posterior cingulate. The risk allele in the Neuregulin 1 (NRG1) promoter region, on the other hand, was associated with the development of psychotic symptoms, decreased premorbid IQ and decreased activation of pre-frontal and temporal lobe regions. The NRG1 gene appears to be a risk factor for an extended or intermediate phenotype, while the COMT Val allele, which decreases the rate at which cortical dopamine is degraded compared to the Met allele, is associated with an increased risk of schizophrenia in subjects at increased familial risk. We provide examples of how these advances in our knowledge could lead to the development of new treatments for psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 128 | Eur. J. Pharmacol. 2008 Apr 583: 215-25 |
| PMID | 18342852 |
| Title | Synaptic physiology of central CRH system. |
| Abstract | Corticotropin-Releasing Hormone (CRH) or Corticotropin-Releasing Factor (CRF) and its family of related naturally occurring endogenous peptides and receptors are becoming recognized for their actions within central (CNS) and peripheral (PNS) nervous systems. It should be recognized that the term 'CRH' has been displaced by 'CRF' [Guillemin, R., 2005. Hypothalamic hormones a.k.a. hypothalamic releasing factors. J. Endocrinol. 184, 11-28]. However, to maintain uniformity among contributions to this special issue we have used the original term, CRH. The term 'CRF' has been associated recently with CRH receptors and designated with subscripts by the IUPHAR nomenclature committee [Hauger, R.L., Grigoriadis, D.E., Dallman, M.F., Plotsky, P.M., Vale, W.W., Dautzenberg, F.M., 2003. International Union of Pharmacology. XXXVI. Corticotrophin-releasing factor and their ligands. Pharmacol. Rev. 55, 21-26] to denote the type and subtype of receptors activated or antagonized by CRH ligands. CRH, as a hormone, has long been identified as the regulator of basal and stress-induced ACTH release within the hypothalamo-pituitary-adrenal axis (HPA axis). But the concept, that CRH and its related endogenous peptides and receptor ligands have non-HPA axis actions to regulate CNS synaptic transmission outside the HPA axis, is just beginning to be recognized and identified [Orozco-Cabal, L., Pollandt, S., Liu, J., Shinnick-Gallagher, P., Gallagher, J.P., 2006a. Regulation of Synaptic Transmission by CRF Receptors. Rev. Neurosci. 17, 279-307; Orozco-Cabal, L., Pollandt, S., Liu, J., Vergara, L., Shinnick-Gallagher, P., Gallagher, J.P., 2006b. A novel rat medial prefrontal cortical slice preparation to investigate synaptic transmission from amygdala to layer V prelimbic pyramidal neurons. J. Neurosci. Methods 151, 148-158] is especially noteworthy since this synapse has become a prime focus for a variety of mental diseases, e.g. schizophrenia [Fischbach, G.D., 2007. NRG1 and synaptic function in the CNS. Neuron 54, 497-497], and neurological disorders, e.g., Alzheimer's disease [Bell, K.F., Cuello, C.A., 2006. Altered synaptic function in Alzheimer's disease. Eur. J. Pharmacol. 545, 11-21]. We suggest that "The Stressed Synapse" has been overlooked [c.f., Kim, J.J., Diamond, D.M. 2002. The stressed hippocampus, synaptic plasticity and lost memories. Nat. Rev., Neurosci. 3, 453-462; Radley, J.J., Morrison, J.H., 2005. Repeated stress and structural plasticity in the brain. Ageing Res. Rev. 4, 271-287] as a major contributor to many CNS disorders. We present data demonstrating CRH neuroregulatory and neuromodulatory actions at three limbic synapses, the basolateral amygdala to central amygdala synapse; the basolateral amygdala to medial prefrontal cortex synapse, and the lateral septum mediolateral nucleus synapse. A novel stress circuit is presented involving these three synapses. We suggest that CRH ligands and their receptors are significant etiological factors that need to be considered in the pharmacotherapy of mental diseases associated with CNS synaptic transmission. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 129 | Brain Struct Funct 2008 Sep 213: 255-71 |
| PMID | 18470533 |
| Title | Age-related changes in the expression of schizophrenia susceptibility genes in the human prefrontal cortex. |
| Abstract | The molecular basis of complex neuropsychiatric disorders most likely involves many genes. In recent years, specific genetic variations influencing risk for schizophrenia and other neuropsychiatric disorders have been reported. We have used custom DNA microarrays and qPCR to investigate the expression of putative schizophrenia susceptibility genes and related genes of interest in the normal human brain. Expression of 31 genes was measured in Brodmann's area 10 (BA10) in the prefrontal cortex of 72 postmortem brain samples spanning half a century of human aging (18-67 years), each without history of neuropsychiatric illness, neurological disease, or drug abuse. Examination of expression across age allowed the identification of genes whose expression patterns correlate with age, as well as genes that share common expression patterns and that possibly participate in common cellular mechanisms related to the emergence of schizophrenia in early adult life. The expression of GRM3 and RGS4 decreased across the entire age range surveyed, while that of PRODH and DARPP-32 was shown to increase with age. NRG1, ERBB3, and NGFR show expression changes during the years of greatest risk for the development of schizophrenia. Expression of FEZ1, GAD1, and RGS4 showed especially high correlation with one another, in addition to the strongest mean levels of absolute correlation with all other genes studied here. All microarray data are available at NCBI's Gene Expression Omnibus: GEO Series accession number GSE11546 (http://www.ncbi.nlm.nih.gov/geo) [corrected] |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 130 | J. Biol. Chem. 2008 Nov 283: 32944-56 |
| PMID | 18819924 |
| Title | ErbB4-neuregulin signaling modulates synapse development and dendritic arborization through distinct mechanisms. |
| Abstract | Perturbations in neuregulin-1 (NRG1)/ErbB4 function have been associated with schizophrenia. Affected patients exhibit altered levels of these proteins and display hypofunction of glutamatergic synapses as well as altered neuronal circuitry. However, the role of NRG1/ErbB4 in regulating synapse maturation and neuronal process formation has not been extensively examined. Here we demonstrate that ErbB4 is expressed in inhibitory interneurons at both excitatory and inhibitory postsynaptic sites. Overexpression of ErbB4 postsynaptically enhances size but not number of presynaptic inputs. Conversely, knockdown of ErbB4 using shRNA decreases the size of presynaptic inputs, demonstrating a specific role for endogenous ErbB4 in synapse maturation. Using ErbB4 mutant constructs, we demonstrate that ErbB4-mediated synapse maturation requires its extracellular domain, whereas its tyrosine kinase activity is dispensable for this process. We also demonstrate that depletion of ErbB4 decreases the number of primary neurites and that stimulation of ErbB4 using a soluble form of NRG1 results in exuberant dendritic arborization through activation of the tyrosine kinase domain of ErbB4 and the phosphoinositide 3-kinase pathway. These findings demonstrate that NRG1/ErbB4 signaling differentially regulates synapse maturation and dendritic morphology via two distinct mechanisms involving trans-synaptic signaling and tyrosine kinase activity, respectively. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 131 | J. Hum. Genet. 2008 -1 53: 929-35 |
| PMID | 18704261 |
| Title | Association and interaction analyses of NRG1 and ERBB4 genes with schizophrenia in a Japanese population. |
| Abstract | Neuregulin 1 (NRG1) is one of the most promising candidate genes for schizophrenia. A number of replication studies have been conducted, although the results were inconsistent and no susceptible variant has yet been identified. The inconsistency might be attributed to the ethnic difference in allele and haplotype frequencies. However, it is equally possible that one or more genes interacting with NRG1 may also be implicated in schizophrenia and attribute to the inconsistency. To test the hypothesis, we conducted an interaction analysis between NRG1 and one of its receptor's (ERBB4) polymorphisms as well as the association analysis of the two genes associated with schizophrenia in Japanese. We observed no significant difference between patients and controls in allele frequencies or genotypic distributions of the 18 polymorphisms of the genes. The permutation test showed no significant differences in estimated haplotype frequencies between patients and controls, including the haplotype HAP(ICE). In the interaction analysis, significant interaction was observed between rs2919381 in NRG1 and rs7560730 in ERBB4 (P = 0.047, corrected). Thus, our results suggest the possibility that interaction between variants in NRG1 and ERBB4 might contribute to susceptibility for schizophrenia in a Japanese population. Further investigation may be necessary to confirm our results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 132 | Schizophr. Res. 2008 Mar 100: 270-80 |
| PMID | 18243664 |
| Title | Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients. |
| Abstract | Neuregulin-1 (NRG1) and its receptor, ErbB4, have been implicated in schizophrenia at both gene and transcript levels. The present investigation compared NRG1 and ErbB4 protein levels in prefrontal cortical (PFC) cytoplasmic and nuclear fractions among normal, schizophrenic, bipolar and major depressed subjects from the Stanley Consortium. We used immunoblotting procedures to examine potential NRG1 and ErbB4 immunoreactive bands, but specifically quantified NRG1 immunoreactive signals at 42, 48 and 53 kDa and ErbB4 immunoreactive signals at 21, 55, 60 and 180 kDa. PFC cytoplasmic 53 kDa NRG1 protein levels were significantly increased (approximately 20%) in schizophrenic patients relative to each of the other subject groups. We also detected diagnostic effects on PFC cytoplasmic full-length (180 kDa) ErbB4 protein levels, and post hoc tests revealed that these quantities were significantly increased (approximately 30%) in schizophrenic patients relative to normal and to depressed subjects. In addition, we examined the levels of potential ErbB4 cleavage products at 21, 55 and 60 kDa relative to those of full-length ErbB4 in the PFC fractions. We detected trends for diagnostic effects on PFC cytoplasmic 21 kDa/180 kDa and 55 kDa/180 kDa ratios, and post hoc tests revealed that these ratios were significantly reduced in schizophrenic patients relative to normal individuals. Our investigation suggests that schizophrenia-associated NRG1 and ErbB4 mRNA elevations also occur at the protein level and may be specific to schizophrenia. We hypothesize that ErbB4 proteolytic processing may also be altered in schizophrenia, yielding altered ratios of functionally distinct forms of ErbB4. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 133 | Arch. Gen. Psychiatry 2008 Jan 65: 53-61 |
| PMID | 18180429 |
| Title | Family-based association study of lithium-related and other candidate genes in bipolar disorder. |
| Abstract | Association studies in bipolar disorder have been focused on a relatively narrow pool of candidate genes based on a limited understanding of the underlying pathophysiologic features. Recent developments suggest that a broader pool of genes may be associated with this disorder. To examine the association between genes related to the lithium mechanism of action, as well as other positional and functional candidates, with bipolar I disorder. We examined a dense set of haplotype-tagging single-nucleotide polymorphisms using a gene-based test of association. Three hundred seventy-nine parent-affected offspring trios. No genes specifically chosen to probe the action of lithium were associated with bipolar disorder. However, gene-based analysis of sialyltransferase 4A (SIAT4A), tachykinin receptor 1 (TACR1), and gamma-aminobutyric acid(A) beta2 receptor subunit (GABRB2) yielded evidence of association (empirical P value, <.005). Among 3 genes associated with schizophrenia or bipolar disorder in multiple previous studies, including dysbindin (DTNBP1), neuregulin (NRG1), and disrupted-in-schizophrenia 1 (DISC1), only DISC1 showed evidence of association in this cohort. In a secondary analysis of these 6 genes among parent-proband trios with a history of psychosis, evidence of the association with SIAT4A was strengthened. These results suggest novel candidates and 1 gene (DISC1) previously associated with schizophrenia that merit further study in bipolar disorder. However, polymorphisms in major lithium-signaling genes do not appear to contribute substantially to bipolar liability. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 134 | Eur Arch Psychiatry Clin Neurosci 2008 Nov 258 Suppl 5: 35-9 |
| PMID | 18985292 |
| Title | Impact of neuregulin-1 on the pathophysiology of schizophrenia in human post-mortem studies. |
| Abstract | To a large extend schizophrenia has been shown to be heritable, with neuregulin-1 (NRG1) one of the candidate genes considered to play a role in the pathophysiology of the disorder. While several polymorphisms within this gene have been reported to be associated with schizophrenia, the impact of NRG1 risk genotypes on disturbed brain function and symptoms of the disease is unknown and might be elucidated using post-mortem studies. Neuregulins are signalling proteins and the NRG1 family encodes at least 15 different splice variants, classified into four isoforms. They play an important role in cell differentiation, migration, myelination and proliferation of oligodendrocytes and neurons. Dysfunction in these processes may be related to neurodevelopmental disturbances in schizophrenia. NRG1 isoforms are differentially expressed in relevant brain regions of schizophrenia patients such as the prefrontal cortex and hippocampus and may contribute to pathophysiological processes. Different NRG1 genotypes have been shown to influence gene expression of isoforms and the risk-associated variants are in primarily non-coding and promoter regions, probably operating by altering gene expression or splicing. In addition, NRG1 regulates the expression of the nicotinic acetylcholine receptor, and expression of the gamma-aminobutyric acid (GABA(A)) and N-methyl-D: -aspartate receptor in the brain. However, the contribution of NRG1 risk genotypes to expression of isoforms and cognitive or psychotic symptoms in patients remain to be investigated in prospective post-mortem studies. In animal models of ischemia/hypoxia, NRG1 has been shown to act as a therapeutic, neuroprotective agent and should be investigated in more detail in transgenic animal models. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 135 | Neuroimage 2008 Oct 42: 1569-76 |
| PMID | 18606232 |
| Title | Genetic variation in the schizophrenia-risk gene neuregulin1 correlates with differences in frontal brain activation in a working memory task in healthy individuals. |
| Abstract | Working memory dysfunctions are a prominent feature in schizophrenia. These impairments have been linked to alterations in prefrontal brain activation with studies reporting hypo- and hyperactivations. Since schizophrenia has a high heritability, it is of interest whether susceptibility genes modulate working memory and its neural correlates. The aim of the present study was to test the influence of the NRG1 schizophrenia susceptibility gene on working memory and its neural correlates in healthy subjects. 429 healthy individuals performed a verbal and a spatial working memory task. A subsample of 85 subjects performed a 2-back version of the Continuous Performance Test (CPT) in a functional MRI study. The NRG1 SNP8NRG221533 (rs35753505) carrier status was determined and correlated with working memory performance and brain activation. There were no effects of genetic status on behavioural performance in the working memory tasks in the 429 subjects and in the fMRI task (n=85). A linear effect of NRG1 SNP8NRG221533 carrier status on neuronal activation emerged in the fMRI experiment. Hyperactivation of the superior frontal gyrus (BA 10) was correlated with the number of risk alleles. The fMRI data suggest that performance measures between groups did not differ due to a compensational activation of BA 10 in risk-allele carriers. Our results are in line with functional imaging studies in patients with schizophrenia, which also showed a differential activation in lateral prefrontal areas. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 136 | J. Hum. Genet. 2008 -1 53: 739-46 |
| PMID | 18584117 |
| Title | Two-stage designs to identify the effects of SNP combinations on complex diseases. |
| Abstract | The genetic basis of complex diseases is expected to be highly heterogeneous, with many disease genes, where each gene by itself has only a small effect. Based on the nonlinear contributions of disease genes across the genome to complex diseases, we introduce the concept of single nucleotide polymorphism (SNP) synergistic blocks. A two-stage approach is applied to detect the genetic association of synergistic blocks with a disease. In the first stage, synergistic blocks associated with a complex disease are identified by clustering SNP patterns and choosing blocks within a cluster that minimize a diversity criterion. In the second stage, a logistic regression model is given for a synergistic block. Using simulated case-control data, we demonstrate that our method has reasonable power to identify gene-gene interactions. To further evaluate the performance of our method, we apply our method to 17 loci of four candidate genes for paranoid schizophrenia in a Chinese population. Five synergistic blocks are found to be associated with schizophrenia, three of which are negatively associated (odds ratio, OR < 0.3, P < 0.05), while the others are positively associated (OR > 2.0, P < 0.05). The mathematical models of these five synergistic blocks are presented. The results suggest that there may be interactive effects for schizophrenia among variants of the genes neuregulin 1 (NRG1, 8p22-p11), G72 (13q34), the regulator of G-protein signaling-4 (RGS4, 1q21-q22) and frizzled 3 (FZD3, 8p21). Using synergistic blocks, we can reduce the dimensionality in a multi-locus association analysis, and evaluate the sizes of interactive effects among multiple disease genes on complex phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 137 | Schizophr. Res. 2008 Aug 103: 178-85 |
| PMID | 18571900 |
| Title | Neuregulin-1 and the P300 waveform--a preliminary association study using a psychosis endophenotype. |
| Abstract | Neuregulin-1 (NRG1) has been put forward as a susceptibility gene for schizophrenia. We investigated the association between Neuregulin-1 and the P300 wave, a schizophrenia endophenotype. Participants were 64 patients with DSM-IV schizophrenia or schizoaffective disorder, 97 of their non psychotic relatives and 35 unrelated controls. The P300 wave was extracted from the electroencephalogram whilst the subjects conducted a two-tone discrimination task. The effect of three markers from the core NRG-1 at-risk haplotype including single nucleotide polymorphism SNP8NRG221533 and two microsatellites (478B14-848 and 420M9-1395) on P300 amplitude and latency was examined using multilevel modelling. Neuregulin-1 SNP8NRG221533 had a significant influence on P300 latency and the higher the number of C alleles carried, the greater the latency delay [Coef.=32.4 ms; 95%CI: 13.2 to 51.6 ms; p=0.001]. There was no association between latency and NRG1 microsatellites or between amplitude and any of the three markers examined. The P300 latency reflects the speed of neural transmission. We hypothesise that variation in NRG1 may convey risk for schizophrenia by disrupting neural connectivity, possibly white matter integrity, and leading to a slower speed of cognitive processing. This is a preliminary finding in a small sample and requires replication. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 138 | Biol. Psychiatry 2008 Sep 64: 419-27 |
| PMID | 18466881 |
| Title | Support for neuregulin 1 as a susceptibility gene for bipolar disorder and schizophrenia. |
| Abstract | There is support that Neuregulin 1 (NRG1) plays a role in susceptibility to schizophrenia but limited evidence for its involvement in bipolar disorder. We wished to investigate further the involvement of NRG1 in schizophrenia and bipolar disorder. We used hierarchical association analysis in parent-offspring trios, 634 with schizophrenia/schizoaffective disorder (SZ/SA) and 243 with bipolar 1 disorder (BP1). The primary analysis was the markers defining the "core Icelandic haplotype" (HAP(ICE)). We undertook polymorphism discovery, additional genotyping, and also explored phenotypic associations, as a secondary analysis aimed at refining the signal. The initial global haplotype test yielded significant evidence for association (p = .01) with SZ/SA and BP1 (p = .004), although HAP(ICE) was not overtransmitted. The marker showing strongest evidence for association in the deCODE studies, SNP8NRG221533, was associated with SZ/SA (p(corrected) = .039) and with BP1 (p(corrected) = .039), with BP1 showing association to the opposite allele as SZ/SA. The pattern of transmission at SNP8NRG221533 was significantly different in SZ/SA than in BP1 (p = .0004). Secondary analyses of markers and phenotypes provided no additional evidence for association to SZ/SA. However, a new marker, rs7014762, was associated with an a priori defined "typical" bipolar phenotype characterized by excellent recovery between episodes and no mood incongruent features (p(corrected) = .003). Our data provide significant levels of support for NRG1 as a susceptibility gene for both major forms of psychosis, and this cannot be interpreted as being due to population stratification. More tentatively, they also might indicate the presence of multiple alleles that influence the psychosis phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 139 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Oct 147B: 1298-300 |
| PMID | 18286587 |
| Title | The neuregulin 1 promoter polymorphism rs6994992 is not associated with chronic schizophrenia or neurocognition. |
| Abstract | The neuregulin 1 (NRG1) promoter single nucleotide polymorphism (SNP) rs6994992 has shown association with decreased activation of frontal and temporal lobe regions, increased risk of psychosis, and decreased premorbid IQ. This SNP is part of a putative schizophrenia risk-associated haplotype and was associated with increased expression of the type IV transcript in postmortem tissue. We tested for association between rs6994992 and chronic schizophrenia by genotyping 738 cases from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and 733 matched controls. We further tested for associations with age at onset and baseline neurocognition in cases with schizophrenia reasoning that these phenotypes might yield results similar to those seen for premorbid IQ. Affection status was weakly associated with rs6994992 genotypes and trended towards association under a recessive model. This association did not survive correction for multiple comparisons and was in the opposite direction than has been reported. There was no association between rs6994992 and age at onset, an estimate of premorbid IQ, or neurocognition at study baseline. We were unable to replicate previous associations of rs6994992 with schizophrenia and, moreover, did not find significant associations with age of onset, an estimate of pre-morbid IQ, or neurocognition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 140 | Schizophr. Res. 2008 Apr 101: 1-8 |
| PMID | 18282690 |
| Title | Failure to replicate the association between NRG1 and schizophrenia using Japanese large sample. |
| Abstract | Systematic linkage disequilibrium (LD) mapping of 8p12-21 in the Icelandic population identified neuregulin 1 (NRG1) as a prime candidate gene for schizophrenia. However, results of replication studies have been inconsistent, and no large sample analyses have been reported. Therefore, we designed this study with the aim of assessing this putative association between schizophrenia and NRG1 (especially HAP(ICE) region and exon region) using a gene-based association approach in the Japanese population. This study was a two-stage association analysis with a different panel of samples, in which the significant association found in the first-set screening samples (1126 cases and 1022 controls) was further assessed in the confirmation samples (1262 cases and 1172 controls, and 166 trio samples). In the first-set scan, 60 SNPs (49 tagging SNPs from HapMap database, four SNPs from other papers, and seven SNPs detected in the mutation scan) were examined. One haplotype showed a significant association in the first-set screening samples (Global P-value=0.0244, uncorrected). However, we could not replicate this association in the following independent confirmation samples. Moreover, we could not find sufficient evidence for association of the haplotype identified as being significant in the first-set samples by imputing ungenotyped SNPs from HapMap database. These results indicate that the positionally and functionally attractive regions of NRG1 are unlikely to contribute to susceptibility to schizophrenia in the Japanese population. Moreover, the nature of our results support that two-stage analysis with large sample size is appropriate to examine the susceptibility genes for common diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 141 | Neuroimage 2008 Apr 40: 712-8 |
| PMID | 18255317 |
| Title | Association of 5' end neuregulin-1 (NRG1) gene variation with subcortical medial frontal microstructure in humans. |
| Abstract | Animal data suggest that the gene neuregulin-1 (NRG1) is involved in neuronal myelination. A haplotype (deCODE) in the 5' end region of the gene was described to double the risk for schizophrenia in an Icelandic population (Stefansson, H., Sigurdsson, E., Steinthorsdottir, V., Bjornsdottir, S., Sigmundsson, T., Ghosh, S., Brynjolfsson, J., Gunnarsdottir, S., Ivarsson, O., Chou, T.T., Hjaltason, O., Birgisdottir, B., Jonsson, H., Gudnadottir, V.G., Gudmundsdottir, E., Bjornsson, A., Ingvarsson, B., Ingason, A., Sigfusson, S., Hardardottir, H., Harvey, R.P., Lai, D., Zhou, M., Brunner, D., Mutel, V., Gonzalo, A., Lemke, G., Sainz, J., Johannesson, G., Andresson, T., Gudbjartsson, D., Manolescu, A., Frigge, M.L., Gurney, M.E., Kong, A., Gulcher, J.R., Petursson, H., Stefansson, K. 2002. Neuregulin-1 and susceptibility to schizophrenia. Am. J. Hum. Genet. 71, 877-892). Of note, there is now increasing evidence of disturbed myelination in this illness--particularly in subcortical frontal lobe white matter (Konrad, A., Winterer, G. 2008. Disturbed structural connectivity in schizophrenia--primary factor in pathology or epiphenomenon? Schiz. Bull. [Electronic publication ahead of print]). Therefore, we investigated with diffusion tensor imaging (DTI) the impact of a tagging single nucleotide polymorphism (SNP) from the deCODE haplotype, i.e., SNP8NRG221533, on fractional anisotropy (FA), which reflects structural integrity of white matter. SNP8NRG221533 was selected because it gave the single best uncorrected association with schizophrenia in the original report by Stefansson et al. (Stefansson, H., Sigurdsson, E., Steinthorsdottir, V., Bjornsdottir, S., Sigmundsson, T., Ghosh, S., Brynjolfsson, J., Gunnarsdottir, S., Ivarsson, O., Chou, T.T., Hjaltason, O., Birgisdottir, B., Jonsson, H., Gudnadottir, V.G., Gudmundsdottir, E., Bjornsson, A., Ingvarsson, B., Ingason, A., Sigfusson, S., Hardardottir, H., Harvey, R.P., Lai, D., Zhou, M., Brunner, D., Mutel, V., Gonzalo, A., Lemke, G., Sainz, J., Johannesson, G., Andresson, T., Gudbjartsson, D., Manolescu, A., Frigge, M.L., Gurney, M.E., Kong, A., Gulcher, J.R., Petursson, H., Stefansson, K. 2002. Neuregulin-1 and susceptibility to schizophrenia. Am. J. Hum. Genet. 71, 877-892). As predicted, we found medial frontal FA to be significantly associated with this NRG1 gene variation. Using voxel-based morphometry (VBM), we could largely exclude the possibility that this genotype effect is indirectly caused by genotype-dependent effects on brain volume. This is the first demonstration that SNP8NRG221533 of the NRG1 gene affects medial frontal white matter microstructure in humans. As the degree of neuronal myelination contributes to structural integrity, our finding further supports a potential role of NRG1 in neuronal myelination in the human brain. By extension, our findings suggest that SNP8NRG221533 may contribute to the risk for the complex polygenic illness schizophrenia via its impact on myelination in frontal lobe white matter. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 142 | Schizophr. Res. 2008 Mar 100: 281-90 |
| PMID | 18234478 |
| Title | Differential RNA expression between schizophrenic patients and controls of the dystrobrevin binding protein 1 and neuregulin 1 genes in immortalized lymphocytes. |
| Abstract | The dystrobrevin binding protein 1 (DTNBP1) and neuregulin 1 (NRG1) genes have been related to schizophrenia (SZ) and bipolar disorder (BP) by several whole-genome linkage and associations studies. Few expression studies in post-mortem brains have also reported a lower or a higher expression of DTNBP1 and NRG1, respectively, in SZ. Since the difficulty to access post-mortem brains, we evaluated RNA expression of DTNBP1 and NRG1 in immortalized lymphocytes of SZ patients and unrelated-family controls. An antipsychotic stimulation was also used to challenge the genetic background of the subjects and enhance differential expression. Immortalized lymphocytes of twelve SZ and twelve controls were grown individually in the presence or not of the antipsychotic olanzapine (Zyprexa; EliLilly). RNA was extracted and pooled in four groups of three SZ and four groups of three controls, and used to probe Agilent 18K microchips. Mean gene expression values were contrasted between SZ and control groups using a T-test. For DTNBP1, RNA expression was lower in SZ than in controls before (-28%; p=0.02) and after (-30%; p=0.01) olanzapine stimulation. Similarly, NRG1 GGF2 isoform showed a lower expression in SZ before (-29%; p=0.04) and after (-33%; p=0.02) olanzapine stimulation. In contrast, NRG1 GGF isoform showed no significant difference between SZ and controls (-7%; p=0.61, +3%; p=0.86, respectively), but was slightly repressed by olanzapine in controls (-8%; p=0.008) but not in SZ (+1%; p=0.91). These results are in agreement with those observed in post-mortem brain when the isoforms involved are considered. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 143 | Hum. Mol. Genet. 2008 Apr 17: 1169-74 |
| PMID | 18182443 |
| Title | Cis- and trans- loci influence expression of the schizophrenia susceptibility gene DTNBP1. |
| Abstract | Susceptibility to complex disease appears to be partly mediated by heritable differences in gene expression. Where cis-acting effects on a gene's expression influence disease susceptibility, other genes containing polymorphism with a trans-acting effect on expression of that gene may also be expected to modulate risk. Use of the expression of an identified disease gene as an endophenotype for quantitative linkage analysis may therefore provide a powerful method for mapping loci that modulate disease susceptibility. We performed genome-wide linkage analysis on expression of dystrobrevin binding protein 1 (DTNBP1), a well-supported susceptibility gene for schizophrenia, in large CEPH pedigrees. We observed genome-wide significant evidence for linkage at the DTNBP1 locus on chromosome 6p22, and demonstrated that this reflects variable cis-acting effects on DTNBP1 expression. In addition, we observed genome-wide suggestive evidence for linkage of DTNBP1 expression to chromosome 8p, suggesting a locus that exerts a trans-acting effect on DTNBP1 expression. The region of linkage to DTNBP1 expression on chromosome 8 is contiguous with linkage findings based upon the clinical schizophrenia phenotype, and contains another well-supported schizophrenia susceptibility gene, neuregulin-1 (NRG1). Our data provide complementary evidence for chromosome 8p as a susceptibility locus for schizophrenia, and suggest that genetic variation within this region may influence risk, at least in part, through effects on DTNBP1 expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 144 | J Psychiatr Res 2008 Mar 42: 278-88 |
| PMID | 17408693 |
| Title | Association of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction. |
| Abstract | Recent reports indicate that DAO, DAOA, DTNBP1, NRG1 and RGS4 are some of the most-replicated genes implicated in susceptibility to schizophrenia. Also, the functions of these genes could converge in a common pathway of glutamate metabolism. The aim of this study was to evaluate if each of these genes, or their interaction, was associated with schizophrenia. A case-control study was conducted in 589 Spanish patients having a diagnosis of schizophrenia, and compared with 617 equivalent control subjects. Several single nucleotide polymorphisms (SNPs) in each gene were determined in all individuals. SNP and haplotype frequencies were compared between cases and controls. The interaction between different SNPs at the same, or at different gene, loci was analyzed by the multifactor dimensionality reduction (MDR) method. We found a new schizophrenia risk and protective haplotypes in intron VII of DTNBP1; one of the most important candidate genes for this disorder, to-date. However, no association was found between DAO, DAOA, NRG1 and RGS4 and schizophrenia. The hypothesis that gene-gene interaction in these five genes could increase the risk for the disorder was not confirmed in the present study. In summary, these results may provide further support for an association between the dysbindin gene (DTNBP1) and schizophrenia, but not between the disease and DAO, DAOA, NRG1 and RGS4 or with the interaction of these genes. In the light of recent data, these results need to be interpreted with caution and future analyses with dense genetic maps are awaited. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 145 | Mol. Psychiatry 2008 Feb 13: 162-72 |
| PMID | 17579610 |
| Title | Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene. |
| Abstract | Neuregulin and the neuregulin receptor ERBB4 have been genetically and functionally implicated in schizophrenia. In this study, we used the yeast two-hybrid system to identify proteins that interact with ERBB4, to identify genes and pathways that might contribute to schizophrenia susceptibility. We identified the MAGI scaffolding proteins as ERBB4-binding proteins. After validating the interaction of MAGI proteins with ERBB4 in mammalian cells, we demonstrated that ERBB4 expression, alone or in combination with ERBB2 or ERBB3, led to the tyrosine phosphorylation of MAGI proteins, and that this could be further enhanced with receptor activation by neuregulin. As MAGI proteins were previously shown to interact with receptor phosphotyrosine phosphatase beta/zeta (RPTPbeta), we postulated that simultaneous binding of MAGI proteins to RPTPbeta and ERBB4 forms a phosphotyrosine kinase/phosphotyrosine phosphatase complex. Studies in cultured cells confirmed both a spatial and functional association between ERBB4, MAGI and RPTPbeta. Given the evidence for this functional association, we examined the genes coding for MAGI and RPTPbeta for genetic association with schizophrenia in a Caucasian United Kingdom case-control cohort (n= approximately 1400). PTPRZ1, which codes for RPTPbeta, showed significant, gene-wide and hypothesis-wide association with schizophrenia in our study (best individual single-nucleotide polymorphism allelic P=0.0003; gene-wide P=0.0064; hypothesis-wide P=0.026). The data provide evidence for a role of PTPRZ1, and for RPTPbeta signaling abnormalities, in the etiology of schizophrenia. Furthermore, the data indicate a role for RPTPbeta in the modulation of ERBB4 signaling that may in turn provide further support for an important role of neuregulin/ERBB4 signaling in the molecular basis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 146 | Schizophr Bull 2008 Jan 34: 72-92 |
| PMID | 17485733 |
| Title | Disturbed structural connectivity in schizophrenia primary factor in pathology or epiphenomenon? |
| Abstract | Indirect evidence for disturbed structural connectivity of subcortical fiber tracts in schizophrenia has been obtained from functional neuroimaging and electrophysiologic studies. During the past few years, new structural imaging methods have become available. Diffusion tensor imaging and magnetization transfer imaging (MTI) have been used to investigate directly whether fiber tract abnormalities are indeed present in schizophrenia. To date, findings are inconsistent that may express problems related to methodological issues and sample size. Also, pathological processes detectable with these new techniques are not yet well understood. Nevertheless, with growing evidence of disturbed structural connectivity, myelination has been in the focus of postmortem investigations. Several studies have shown a significant reduction of oligodendroglial cells and ultrastructural alterations of myelin sheats in schizophrenia. There is also growing evidence for abnormal expression of myelin-related genes in schizophrenia: Neuregulin (NRG1) is important for oligodendrocyte development and function, and altered expression of erbB3, one of the NRG1 receptors, has been shown in schizophrenia patients. This is consistent with recent genetic studies suggesting that NRG1 may contribute to the genetic risk for schizophrenia. In conclusion, there is increasing evidence from multiple sides that structural connectivity might be pathologically changed in schizophrenia illness. Up to the present, however, it has not been possible to decide whether alterations of structural connectivity are intrinsically linked to the primary risk factors for schizophrenia or to secondary downstream effects (ie, degeneration of fibers secondarily caused by cortical neuronal dysfunction)-an issue that needs to be clarified by future research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 147 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Feb 32: 462-6 |
| PMID | 17980471 |
| Title | Disruption to social dyadic interactions but not emotional/anxiety-related behaviour in mice with heterozygous 'knockout' of the schizophrenia risk gene neuregulin-1. |
| Abstract | Clinical genetic studies have implicated neuregulin-1 [NRG1] as a leading susceptibility gene for schizophrenia. NRG1 is known to play a significant role in the developing brain, which is consistent with the prevailing neurodevelopmental model of schizophrenia. Thus, the emotional and social phenotype of adult mice with heterozygous 'knockout' of transmembrane [TM]-domain NRG1 was examined further in both sexes. Emotional/anxiety-related behaviour was assessed using the elevated plus-maze and the light-dark test. Social behaviour was examined in terms of dyadic interactions between NRG1 mutants and an unfamiliar C57BL6 conspecific in a novel environment. There was no effect of NRG1 genotype on performance in either test of emotionality/anxiety. However, previous reports of hyperactivity in NRG1 mutants were confirmed in both paradigms. In the test of social interaction, aggressive following was increased in NRG1 mutants of both sexes, together with an increase in walkovers in female mutants. These findings elaborate the specificity of the NRG1 phenotype for the social rather than the emotional/anxiety-related domain. They indicate that NRG1 is involved in the regulation of reciprocal social interaction behaviour and thus suggest a putative role for NRG1 in a schizophrenia-related endophenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 148 | Biol. Psychiatry 2008 Jan 63: 17-23 |
| PMID | 17631867 |
| Title | Evidence of missense mutations on the neuregulin 1 gene affecting function of prepulse inhibition. |
| Abstract | Neuregulin 1 (NRG1) is one of the leading candidate genes in schizophrenia. Rodents with NRG1 knock-out showed significantly impaired prepulse inhibition (PPI) in the original report linking NRG1 to schizophrenia. A widely used surrogate measure of psychosis in animal models, PPI is considered a schizophrenia endophenotype. We hypothesized that if NRG1 influences PPI in rodents, then it should have a similar effect on PPI in humans. We examined the potential neurophysiological effects of two nonsynonymous single nucleotide polymorphisms located on NRG1 (rs3924999 and rs10503929) on PPI. Genotyping was completed in 430 unrelated individuals, including 244 schizophrenia cases and 186 controls. PPI was available in a subgroup of 113 cases and 63 controls. Rs3924999 genotype was significantly associated with PPI (p = .003): PPI was lowest in the subjects who were homozygous for the minor allele A/A carriers, intermediate in A/G carriers, and highest in homozygous major alleles G/G carriers. The associations persisted within cases (p = .02) and controls (p = .02) analyzed separately. An additive model suggested that rs3924999 alone contributes to 7.9% of the PPI variance. In contrast, rs10503929 genotype was not associated with PPI (p = .85). schizophrenia patients had reduced PPI compared to control subjects (p = .04). Neither single nucleotide polymorphism was associated with schizophrenia (all p > .37). However, schizophrenia patients with abnormal PPI may be associated with rs3924999 (p = .05). A missense mutation on rs3924999 of the neuregulin 1 gene may have a functional effect on prepulse inhibition in both schizophrenia and healthy control populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 149 | Schizophr. Res. 2008 Mar 100: 270-80 |
| PMID | 18243664 |
| Title | Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients. |
| Abstract | Neuregulin-1 (NRG1) and its receptor, ErbB4, have been implicated in schizophrenia at both gene and transcript levels. The present investigation compared NRG1 and ErbB4 protein levels in prefrontal cortical (PFC) cytoplasmic and nuclear fractions among normal, schizophrenic, bipolar and major depressed subjects from the Stanley Consortium. We used immunoblotting procedures to examine potential NRG1 and ErbB4 immunoreactive bands, but specifically quantified NRG1 immunoreactive signals at 42, 48 and 53 kDa and ErbB4 immunoreactive signals at 21, 55, 60 and 180 kDa. PFC cytoplasmic 53 kDa NRG1 protein levels were significantly increased (approximately 20%) in schizophrenic patients relative to each of the other subject groups. We also detected diagnostic effects on PFC cytoplasmic full-length (180 kDa) ErbB4 protein levels, and post hoc tests revealed that these quantities were significantly increased (approximately 30%) in schizophrenic patients relative to normal and to depressed subjects. In addition, we examined the levels of potential ErbB4 cleavage products at 21, 55 and 60 kDa relative to those of full-length ErbB4 in the PFC fractions. We detected trends for diagnostic effects on PFC cytoplasmic 21 kDa/180 kDa and 55 kDa/180 kDa ratios, and post hoc tests revealed that these ratios were significantly reduced in schizophrenic patients relative to normal individuals. Our investigation suggests that schizophrenia-associated NRG1 and ErbB4 mRNA elevations also occur at the protein level and may be specific to schizophrenia. We hypothesize that ErbB4 proteolytic processing may also be altered in schizophrenia, yielding altered ratios of functionally distinct forms of ErbB4. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 150 | Schizophr. Res. 2008 Mar 100: 281-90 |
| PMID | 18234478 |
| Title | Differential RNA expression between schizophrenic patients and controls of the dystrobrevin binding protein 1 and neuregulin 1 genes in immortalized lymphocytes. |
| Abstract | The dystrobrevin binding protein 1 (DTNBP1) and neuregulin 1 (NRG1) genes have been related to schizophrenia (SZ) and bipolar disorder (BP) by several whole-genome linkage and associations studies. Few expression studies in post-mortem brains have also reported a lower or a higher expression of DTNBP1 and NRG1, respectively, in SZ. Since the difficulty to access post-mortem brains, we evaluated RNA expression of DTNBP1 and NRG1 in immortalized lymphocytes of SZ patients and unrelated-family controls. An antipsychotic stimulation was also used to challenge the genetic background of the subjects and enhance differential expression. Immortalized lymphocytes of twelve SZ and twelve controls were grown individually in the presence or not of the antipsychotic olanzapine (Zyprexa; EliLilly). RNA was extracted and pooled in four groups of three SZ and four groups of three controls, and used to probe Agilent 18K microchips. Mean gene expression values were contrasted between SZ and control groups using a T-test. For DTNBP1, RNA expression was lower in SZ than in controls before (-28%; p=0.02) and after (-30%; p=0.01) olanzapine stimulation. Similarly, NRG1 GGF2 isoform showed a lower expression in SZ before (-29%; p=0.04) and after (-33%; p=0.02) olanzapine stimulation. In contrast, NRG1 GGF isoform showed no significant difference between SZ and controls (-7%; p=0.61, +3%; p=0.86, respectively), but was slightly repressed by olanzapine in controls (-8%; p=0.008) but not in SZ (+1%; p=0.91). These results are in agreement with those observed in post-mortem brain when the isoforms involved are considered. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 151 | Mol. Psychiatry 2009 Aug 14: 741-3 |
| PMID | 19626024 |
| Title | A 5' promoter region SNP in NRG1 is associated with schizophrenia risk and type III isoform expression. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 152 | J Neurodev Disord 2009 Dec 1: 302-12 |
| PMID | 21547722 |
| Title | Deficient NRG1-ERBB signaling alters social approach: relevance to genetic mouse models of schizophrenia. |
| Abstract | Growth factor Neuregulin 1 (NRG1) plays an essential role in development and organization of the cerebral cortex. NRG1 and its receptors, ERBB3 and ERBB4, have been implicated in genetic susceptibility for schizophrenia. Disease symptoms include asociality and altered social interaction. To investigate the role of NRG1-ERBB signaling in social behavior, mice heterozygous for an NRG1 null allele (NRG1+/-), and mice with conditional ablation of Erbb3 or Erbb4 in the central nervous system, were evaluated for sociability and social novelty preference in a three-chambered choice task. Results showed that deficiencies in NRG1 or ERBB3 significantly enhanced sociability. All of the mutant groups demonstrated a lack of social novelty preference, in contrast to their respective wild-type controls. Effects of NRG1, ERBB3, or ERBB4 deficiency on social behavior could not be attributed to general changes in anxiety-like behavior, activity, or loss of olfactory ability. NRG1+/- pups did not exhibit changes in isolation-induced ultrasonic vocalizations, a measure of emotional reactivity. Overall, these findings provide evidence that social behavior is mediated by NRG1-ERBB signaling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 153 | Genet. Mol. Biol. 2009 Oct 32: 729-30 |
| PMID | 21637446 |
| Title | Schizophrenia is not associated with the ERBB3 gene in a Han Chinese population sample: Results from case-control and family-based studies. |
| Abstract | ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3), encoding a receptor of neuregulin-1 (NRG1), has been considered a functional candidate gene for schizophrenia susceptibility. In order to investigate a relationship between ERBB3 gene and schizophrenia in the Chinese population, case-control and family-based studies were carried out in 470 cases matched by controls, and in 532 family trios. Our results failed to show any evidence of significant association between the ERBB3 rs2292238 polymorphism and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 154 | Fa Yi Xue Za Zhi 2009 Oct 25: 348-51, 358 |
| PMID | 20000043 |
| Title | [The correlation between ketamine-induced schizophrenia-like signs in mice and the expressions of NRG1, ErbB4 mRNA]. |
| Abstract | To explore the correlation between signs similar to schizophrenia in mice after ketamine administration and the expressions of NRG1 and ErbB4 mRNA in order to explain the possible pathogenesis of schizophrenia. Fifty KM mice were randomly divided into 5 groups which were administered intraperitoneally with saline, clozapine and different dosages ketamine. The ketamine groups were administered intraperitoneally with low dosage (25 mg/kg), middle dosage (50 mg/kg) and high dosage (100 mg/kg) one time every day for 7 days. After administration of 100 mg/kg ketamine for 7 days, the clozapine group was introgastrically administered 20 mg/kg with clozapine one time every day for 7 days. The pathological changes of hippocampus neurons were observed by HE stain. The expressions of the NRG1 and ErbB4 mRNA in hippocampus were detected by reverse transcriptase polymerase chain reaction (RT-PCR). In the group with high dosage of ketamine, the levels of NRG1 and ErbB4 mRNA were significantly lower than that of the group with saline. Ketamine may induce signs similar to schizophrenia in KM mice. The mechanism may be involved in the reduction of NRG1 and ErbB4 mRNA expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 155 | Neuroreport 2009 Nov 20: 1523-8 |
| PMID | 19829162 |
| Title | Behavioural characterization of neuregulin 1 type I overexpressing transgenic mice. |
| Abstract | Neuregulin 1 (NRG1) is a pleiotropic growth factor involved in diverse aspects of brain development and function. In schizophrenia, expression of the NRG1 type I isoform is selectively increased. However, virtually nothing is known about the roles of this isoform in brain. We have studied transgenic mice overexpressing type I NRG1(NRG1type 1-tg) using a series of behavioural tests. NRG1(type 1-tg) mice have a tremor, are impaired on the accelerating rotarod, and have reduced prepulse inhibition in the context of an increased baseline startle response. There is no overall anxiety or activity phenotype, although female NRG(1type 1-tg) mice show mild increases in anxiety on some measures. The pattern of results shows both similarities and differences to those reported in hypomorphic NRG1 mice, and may be relevant for interpreting the increased NRG1 type I expression observed in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 156 | J Psychiatr Res 2009 Oct 43: 1195-9 |
| PMID | 19435634 |
| Title | Three-cohort targeted gene screening reveals a non-synonymous TRKA polymorphism associated with schizophrenia. |
| Abstract | schizophrenia is a complex neurodevelopmental disorder that is thought to be induced by an interaction between predisposing genes and environmental stressors. To identify predisposing genetic factors, we performed a targeted (mostly neurodevelopmental) gene approach involving the screening of 396 selected non-synonymous single-nucleotide polymorphisms (SNPs) in three independent Caucasian schizophrenia case-control cohorts (USA, Denmark and Norway). A meta-analysis revealed ten non-synonymous SNPs that were nominally associated with schizophrenia, nine of which have not been previously linked to the disorder. Risk alleles are in TRKA (rs6336), BARD1 (rs28997576), LAMA5 (rs3810548), DKK2 (rs7037102), NOD2 (rs2066844) and RELN (rs2229860), whereas protective alleles are in NOD2 (rs2066845), NRG1 (rs10503929), ADAM7 (rs13259668) and TNR (rs859427). Following correction for multiple testing, the most attractive candidate for further study concerns SNP rs6336 (q=0.12) that causes the substitution of an evolutionarily highly conserved amino acid residue in the kinase domain of the neurodevelopmentally important receptor TRKA. Thus, TRKA signaling may represent a novel susceptibility pathway for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 157 | Neuropsychobiology 2009 -1 59: 142-50 |
| PMID | 19439994 |
| Title | DTNBP1, NRG1, DAOA, DAO and GRM3 polymorphisms and schizophrenia: an association study. |
| Abstract | Several studies of the dystrobrevin-binding protein 1 gene (DTNBP1), neuregulin 1 (NRG1), D-amino-acid oxidase (DAO), DAO activator (DAOA, G72), and metabotropic glutamate receptor 3 (GRM3) genes have suggested an association between variants of these genes and schizophrenia. In a replication attempt, single-nucleotide polymorphisms of the DTNBP1, NRG1, DAO, DAOA, and GRM3 genes were analyzed in three independent Scandinavian schizophrenia case-control samples. One DTNBP1 and three GRM3 single-nucleotide polymorphisms showed nominal significant associations to the disease. However, after correction for multiple testing, there were no statistically significant allele, genotype or haplotype case-control differences. The present Scandinavian results do not verify previous associations between the analyzed DTNBP1, NRG1, DAO, DAOA, and GRM3 gene polymorphisms and schizophrenia. Additional studies and meta-analyses are warranted to shed further light on these relationships. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 158 | Exp. Cell Res. 2009 Feb 315: 611-8 |
| PMID | 19046966 |
| Title | ErbB receptors and the development of the nervous system. |
| Abstract | Tyrosine kinase receptors and their ligands allow communication between cells in the developing and adult organism. An extensive line of research has revealed that 'neuregulins', a family of EGF-like factors that signal via ErbB receptors, are used frequently for cell communication during nervous system development, and control a spectacular spectrum of developmental processes. For instance, during development of the peripheral nervous system, Schwann cells require neuronally-produced neuregulin (NRG1) for growth, migration and myelination, neural crest cells rely on mesenchymally-generated NRG1 signals for migration, while muscle requires neuronally-produced NRG1 for the differentiation of a muscle spindle. In the central nervous system, neuregulin signals allow cells to act as guideposts or as barriers for axons during pathfinding. Neuregulin signals are also important in other organs, but the nervous system functions have received recently considerable attention due to the finding that particular haplotypes of NRG1 and ErbB4 predispose to schizophrenia. Understanding the neuregulin signaling system can thus contribute to define causes of this devastating mental disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 159 | Proc. Natl. Acad. Sci. U.S.A. 2009 Mar 106: 4507-12 |
| PMID | 19240213 |
| Title | Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system. |
| Abstract | Neuregulin-1 (NRG1) and its ErbB2/B4 receptors are encoded by candidate susceptibility genes for schizophrenia, yet the essential functions of NRG1 signaling in the CNS are still unclear. Using CRE/LOX technology, we have inactivated ErbB2/B4-mediated NRG1 signaling specifically in the CNS. In contrast to expectations, cell layers in the cerebral cortex, hippocampus, and cerebellum develop normally in the mutant mice. Instead, loss of ErbB2/B4 impairs dendritic spine maturation and perturbs interactions of postsynaptic scaffold proteins with glutamate receptors. Conversely, increased NRG1 levels promote spine maturation. ErbB2/B4-deficient mice show increased aggression and reduced prepulse inhibition. Treatment with the antipsychotic drug clozapine reverses the behavioral and spine defects. We conclude that ErbB2/B4-mediated NRG1 signaling modulates dendritic spine maturation, and that defects at glutamatergic synapses likely contribute to the behavioral abnormalities in ErbB2/B4-deficient mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 160 | Curr. Mol. Med. 2009 May 9: 506-18 |
| PMID | 19519407 |
| Title | The role of genes involved in neuroplasticity and neurogenesis in the observation of a gene-environment interaction (GxE) in schizophrenia. |
| Abstract | schizophrenia is a multifactorial disease characterized by a high heritability. Several candidate genes have been suggested, with the strongest evidences for genes encoding dystrobrevin binding protein 1 (DTNBP1), neuregulin 1 (NRG1), neuregulin 1 receptor (ERBB4) and disrupted in schizophrenia 1 (DISC1), as well as several neurotrophic factors. These genes are involved in neuronal plasticity and play also a role in adult neurogenesis. Therefore, the genetic basis of schizophrenia could involve different factors more or less specifically required for neuroplasticity, including the synapse maturation, potentiation and plasticity as well as neurogenesis. Following the model of Knudson in tumors, we propose a two-hit hypothesis of schizophrenia. In this model of gene-environment interaction, a variant in a gene related to neurogenesis is transmitted to the descent (first hit), and, secondarily, an environmental factor occurs during the development of the central nervous system (second hit). Both of these vulnerability and trigger factors are probably necessary to generate a deficit in neurogenesis and therefore to cause schizophrenia. The literature supporting this gene x environment hypothesis is reviewed, with emphasis on some molecular pathways, raising the possibility to propose more specific molecular medicine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 161 | Prog. Brain Res. 2009 -1 179: 75-86 |
| PMID | 20302820 |
| Title | Gene models of schizophrenia: DISC1 mouse models. |
| Abstract | Disrupted in schizophrenia-1 (DISC1) is one of the most likely susceptibility genes for schizophrenia (SZ). DISC1 is being established as a hub protein with various functions in the pre- and postnatal development of the nervous system. Since generation of a knockout (KO) mouse has proved challenging, various alternative approaches have been taken. Seven DISC1 mouse models have been described to date. All of them display neuroanatomical and behavioral abnormalities relevant to SZ, although most of them have not been fully characterized yet, requiring further analysis. NRG1 and ErbB4, also highly promising susceptibility genes for SZ, share many features with DISC1. They are involved in various aspects of pre- and postnatal neurodevelopment. The NRG1 and ErbB4 mouse models also display neuroanatomical and behavioral abnormalities similar to the DISC1 mouse models. In the future, four main directions need further study. First, further characterization of the seven DISC1 mouse models, especially in light of basic research findings. Second, more extensive employment of the inducible models. Third, generation of a DISC1 KO. Fourth, combination of the DISC1 mouse models with other risk factors: crossing with other genetic models such as NRG1/ErbB4 mutants and exposure to environmental risk factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 162 | Curr Opin Psychiatry 2009 Mar 22: 154-60 |
| PMID | 19553869 |
| Title | Recent advances in postmortem pathology and neurochemistry in schizophrenia. |
| Abstract | This is a review examining recent data from the study of the postmortem central nervous system (CNS) of patients with schizophrenia. Studies on the human CNS transcriptome suggest changes in pro-inflammatory pathways and myelination in schizophrenia, whereas changes in the proteome suggest that pathways involved in energy and metabolism may be particularly stressed. There appear to be complex changes in the expression of proposed candidate genes for schizophrenia such as NRG1, DISC1, RGS4 and DTNB1, and there are continued reports of alterations in central gamma-aminobutyric acidergic, dopaminergic, glutamatergic and cholinergic pathways in patients with the disorder. Data on epigenetic mechanisms and transcriptome regulation suggest that at least some changes in gene expression may be due to changes in levels of gene promoter methylation or microRNAs in the CNS of patients with schizophrenia. Postmortem CNS studies have begun to unravel changes in the epigenetic regulation of gene expression that may be central to how gene-environment interactions contribute to the onset of schizophrenia. In addition, a recent study indicates that it is possible to use biomarkers to segregate the syndrome of schizophrenia into more biologically homogeneous populations, which should decrease the biological complexity observed within that group within the schizophrenia syndrome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 163 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Aug 33: 903-5 |
| PMID | 19394386 |
| Title | Genetic association analysis of NRG1 with methamphetamine-induced psychosis in a Japanese population. |
| Abstract | The neuregulin 1 gene (NRG1) has been identified as a candidate gene for schizophrenia in a linkage study in the Icelandic population. Recent evidence also suggested that it might be related to the neurodevelopmental hypothesis and glutamate hypothesis for schizophrenia. Because the symptomatology of methamphetamine (METH) use disorder with accompanying psychosis is similar to that of patients with schizophrenia, NRG1 is an appropriate candidate gene for METH-induced psychosis. We conducted a case-control association study between NRG1 and METH-induced psychosis in a Japanese population (184 subjects with METH-induced psychosis and 534 controls). Written informed consent was obtained from each subject. We selected four SNPs (SNP8NRG221533, SNP8NRG241930, SNP8NRG243177, and rs3924999) in NRG1 from previous reports. No significant association was found between NRG1 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, NRG1 might not contribute to the risk of METH-induced psychosis in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 164 | J Neural Transm (Vienna) 2009 Apr 116: 479-86 |
| PMID | 19184335 |
| Title | Neuregulin 1 and age of onset in the major psychoses. |
| Abstract | Genetic vulnerability to psychiatric illness extends across major psychiatric illness. Neuregulin 1 (NRG1) is a large gene on chromosome 8p, that has been identified as a susceptibility factor in bipolar disorder and schizophrenia. In particular, a core at risk haplotype has received considerable attention for a putative role in the pathophysiology of the major psychoses (schizophrenia and bipolar disorder). This core haplotype can be represented by three markers 478B14-848, 420M9-1395, and SNP8NRG221533. We genotyped 312 families with bipolar probands, and 120 families with schizophrenia probands. Association of the core haplotype was tested for with age-at-onset and with three phenotypes: major psychosis, schizophrenia, and bipolar disorder. Neither age of onset (P = 0.893) nor the major psychosis phenotype (P = 0.374) was associated with the core haplotype in the overall sample. Ours was the first study to investigate the NRG1 core haplotype with age of onset of major psychoses, and despite our preliminary negative findings, this area deserves further investigation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 165 | Biochem. Soc. Trans. 2009 Feb 37: 308-12 |
| PMID | 19143653 |
| Title | Mutant models for genes associated with schizophrenia. |
| Abstract | schizophrenia is a highly complex and heritable psychiatric disorder in which multiple genes and environmental factors interact to cause the schizophrenia phenotype. A new generation of molecular studies has yielded numerous candidate genes with a putative role in risk for schizophrenia, whereas other genes regulate putative pathophysiological mechanisms. Mutant mice having either deletion (knockout) or insertion (knockin/transgenesis) of schizophrenia risk genes now allow the functional role of these genes to be investigated. In the present mini-review, we outline the advantages and limitations of various approaches to phenotypic assessment of mutant mouse models, including ethologically based methods. Thereafter, we consider recent findings, with a particular focus on, first, dopaminergic and glutamatergic pathophysiological models and, secondly, putative roles for DISC1 (disrupted in schizophrenia 1) and NRG1 (neuregulin 1) as susceptibility genes for schizophrenia. Finally, we identify current challenges associated with the use of genetic mutant models and highlight their potential value for exploring gene-gene and gene-environment interactions in relation to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 166 | Int Rev Psychiatry 2009 -1 21: 387-93 |
| PMID | 20374152 |
| Title | Genetic risk for white matter abnormalities in bipolar disorder. |
| Abstract | White matter deficits have been demonstrated in people with bipolar disorder, schizophrenia and their unaffected relatives. These deficits are supported by evidence from post-mortem studies, including microarray investigations which have repeatedly implicated abnormal myelin-associated gene expression. Furthermore, several risk-associated genes have now been identified that encode for proteins which have effects on white matter integrity. These genes include neuregulin-1 (NRG1) polymorphisms of which have been associated with risk to bipolar disorder. NRG1 has been shown to have effects on axonal migration, myelination and oligodendrocyte function. We and others have also shown that 5' risk-associated genetic variants in NRG1 are associated with reductions in both white matter density and integrity in regions associated with prefrontal connectivity. These findings are discussed in the context of the current literature, along with possible future research directions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 167 | Eur Arch Psychiatry Clin Neurosci 2009 Mar 259: 72-9 |
| PMID | 18806920 |
| Title | Neuregulin 1 ICE-single nucleotide polymorphism in first episode schizophrenia correlates with cerebral activation in fronto-temporal areas. |
| Abstract | The Neuregulin (NRG1) gene has been associated with schizophrenia, but its functional implications are largely unknown. Our aim was to assess differential brain activation between patients carrying an at-risk allele on the Neuregulin 1 gene and patients without this genetic risk. Neural signal changes between 14 first episode schizophrenia patients with the at risk allele (SNP8NRG221533) from the Icelandic core haplotype and 14 without were measured with fMRI during a working memory task. Patients without the at risk allele showed greater activations (P < 0.05; corrected) in the left hippocampus, precuneus and cerebellum, as well as the right anterior cingulate. Brain regions previously associated with the pathology of schizophrenia are differentially affected in those with a genetic at risk status in the NRG1 gene. Heterogeneity of structural and functional measures within patients characterized by clinical phenotypes may be in part due to this genetic variation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 168 | Psychol Med 2009 Nov 39: 1783-97 |
| PMID | 19573260 |
| Title | The effect of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on hippocampal and lateral ventricular volume in psychosis. |
| Abstract | Morphometric endophenotypes which have been proposed for psychotic disorders include lateral ventricular enlargement and hippocampal volume reductions. Genetic epidemiological studies support an overlap between schizophrenia and bipolar disorder, and COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes have been implicated in the aetiology of both these disorders. This study examined associations between these candidate genes and morphometric endophenotypes for psychosis. A total of 383 subjects (128 patients with psychosis, 194 of their unaffected relatives and 61 healthy controls) from the Maudsley Family Psychosis Study underwent structural magnetic resonance imaging and genotyping. The effect of candidate genes on brain morphometry was examined using linear regression models adjusting for clinical group, age, sex and correlations between members of the same family. The results showed no evidence of association between variation in COMT genotype and lateral ventricular, and left or right hippocampal volumes. Neither was there any effect of the BDNF, 5-HTTLPR, NRG1 and DTNBP1 genotypes on these regional brain volumes. Abnormal hippocampal and lateral ventricular volumes are among the most replicated endophenotypes for psychosis; however, the influences of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on these key brain regions must be very subtle if at all present. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 169 | J. Neurosci. 2009 Sep 29: 12255-64 |
| PMID | 19793984 |
| Title | Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus. |
| Abstract | NRG1 and ERBB4 have emerged as some of the most reproducible schizophrenia risk genes. Moreover, the Neuregulin (NRG)/ErbB4 signaling pathway has been implicated in dendritic spine morphogenesis, glutamatergic synaptic plasticity, and neural network control. However, despite much attention this pathway and its effects on pyramidal cells have received recently, the presence of ErbB4 in these cells is still controversial. As knowledge of the precise locus of receptor expression is crucial to delineating the mechanisms by which NRG signaling elicits its diverse physiological effects, we have undertaken a thorough analysis of ErbB4 distribution in the CA1 area of the rodent hippocampus using newly generated rabbit monoclonal antibodies and ErbB4-mutant mice as negative controls. We detected ErbB4 immunoreactivity in GABAergic interneurons but not in pyramidal neurons, a finding that was further corroborated by the lack of ErbB4 mRNA in electrophysiologically identified pyramidal neurons as determined by single-cell reverse transcription-PCR. Contrary to some previous reports, we also did not detect processed ErbB4 fragments or nuclear ErbB4 immunoreactivity. Ultrastructural analysis in CA1 interneurons using immunoelectron microscopy revealed abundant ErbB4 expression in the somatodendritic compartment in which it accumulates at, and adjacent to, glutamatergic postsynaptic sites. In contrast, we found no evidence for presynaptic expression in cultured GAD67-positive hippocampal interneurons and in CA1 basket cell terminals. Our findings identify ErbB4-expressing interneurons, but not pyramidal neurons, as a primary target of NRG signaling in the hippocampus and, furthermore, implicate ErbB4 as a selective marker for glutamatergic synapses on inhibitory interneurons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 170 | Trends Neurosci. 2009 Sep 32: 485-95 |
| PMID | 19712980 |
| Title | Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1. |
| Abstract | schizophrenia (SZ) is primarily an adult psychiatric disorder in which disturbances caused by susceptibility genes and environmental insults during early neurodevelopment initiate neurophysiological changes over a long time course, culminating in the onset of full-blown disease nearly two decades later. Aberrant postnatal brain maturation is an essential mechanism underlying the disease. Currently, symptoms of SZ are treated with anti-psychotic medications that have variable efficacy and severe side effects. There has been much interest in the prodromal phase and the possibility of preventing SZ by interfering with the aberrant postnatal brain maturation associated with this disorder. Thus, it is crucial to understand the mechanisms that underlie the long-term progression to full disease manifestation to identify the best targets and approaches towards this goal. We believe that studies of certain SZ genetic susceptibility factors with neurodevelopmental implications will be key tools in this task. Accumulating evidence suggests that neuregulin-1 (NRG1) and disrupted-in-schizophrenia-1 (DISC1) are probably functionally convergent and play key roles in brain development. We provide an update on the role of these emerging concepts in understanding the complex time course of SZ from early neurodevelopmental disturbances to later onset and suggest ways of testing these in the future. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 171 | Biol. Psychiatry 2009 Dec 66: 990-6 |
| PMID | 19782967 |
| Title | Mixture model clustering of phenotype features reveals evidence for association of DTNBP1 to a specific subtype of schizophrenia. |
| Abstract | While DTNBP1, DISC1, and NRG1 have been extensively studied as candidate genes of schizophrenia, results remain inconclusive. Possible explanations for this are that the genes might be relevant only to certain subtypes of the disease and/or only in certain populations. We performed unsupervised clustering of individuals from Finnish schizophrenia families, based on extensive clinical and neuropsychological data, including Structured Clinical Interview for DSM-IV (SCID) information. Families with at least one affected member with DSM-IV diagnosis of a schizophrenia spectrum psychosis were included in a register-based ascertainment. Final sample consisted of 904 individuals from 288 families. We then used the cluster phenotypes in a genetic association study of candidate genes. A robust three-class clustering of individuals emerged: 1) psychotic disorder with mood symptoms (n = 172), 2) core schizophrenia (n = 223), and 3) absence of psychotic disorder (n = 509). One third of the individuals diagnosed with schizophrenia were assigned to cluster 1. These individuals had fewer negative and positive psychotic symptoms and cognitive deficits but more depressive symptoms than individuals in cluster 2. There was a significant association of cluster 2 cases with the DTNBP1 gene, while the DISC1 gene indicated a significant association with schizophrenia spectrum disorders based on the DSM-IV criteria. In the Finnish population, DTNBP1 gene is associated with a schizophrenia phenotype characterized by prominent negative symptoms, generalized cognitive impairment, and few mood symptoms. Identification of genes and pathways related to schizophrenia necessitates novel definitions of disease phenotypes associated more directly with underlying biology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 172 | Arch. Gen. Psychiatry 2009 Aug 66: 828-37 |
| PMID | 19652122 |
| Title | Support for NRG1 as a susceptibility factor for schizophrenia in a northern Swedish isolated population. |
| Abstract | Neuregulin 1 (NRG1), a growth factor involved in neurodevelopment, myelination, neurotransmitter receptor expression, and synaptic plasticity, first joined the list of candidate genes for schizophrenia when a 7-marker haplotype at the 5' end of the gene (Hap(ICE)) was shown to be associated with the disorder in the Icelandic population. Since then, more genetic and functional evidence has emerged, which supports a role for NRG1 in the development of schizophrenia. To determine the contribution of NRG1 to susceptibility for schizophrenia in a northern Swedish isolated population. Detailed linkage disequilibrium (LD)-based patient-control association study. This is the first study to type and analyze the 7 Hap(ICE) markers and a set of 32 HapMap tagging single-nucleotide polymorphisms (SNPs) that represents variants with a minor allele frequency of at least 1% and fully characterizes the LD structure of the 5' part of NRG1. Outpatient and inpatient hospitals. A total of 486 unrelated patients with schizophrenia and 514 unrelated control individuals recruited from a northern Swedish isolated population. Association between markers and disease. Analysis of the Hap(ICE) markers showed the association of a 7-marker and 2-microsatellite haplotype, different from the haplotypes associated in the Icelandic population and overrepresented in northern Swedish control individuals. Subsequently, a more detailed analysis that included all 37 genotyped SNPs was performed by investigating haplotypic association, dependent and independent of LD block structure. We found significant association with 5 SNPs located in the second intron of NRG1 (.007 The NRG1 gene contributes to the susceptibility for schizophrenia in the northern Swedish population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 173 | Brain Res. 2009 Oct 1294: 116-27 |
| PMID | 19643092 |
| Title | Neuregulin 1 transgenic mice display reduced mismatch negativity, contextual fear conditioning and social interactions. |
| Abstract | Neuregulin-1 (NRG1) is one of susceptibility genes for schizophrenia and plays critical roles in glutamatergic, dopaminergic and GABAergic signaling. Using mutant mice heterozygous for NRG1 (NRG1(+/-)) we studied the effects of NRG1 signaling on behavioral and electrophysiological measures relevant to schizophrenia. Behavior of NRG1(+/-) mice and their wild type littermates was evaluated using pre-pulse inhibition, contextual fear conditioning, novel object recognition, locomotor, and social choice paradigms. Event-related potentials (ERPs) were recorded to assess auditory gating and novel stimulus detection. Gating of ERPs was unaffected in NRG1(+/-) mice, but mismatch negativity in response to novel stimuli was attenuated. The NRG1(+/-) mice exhibited behavioral deficits in contextual fear conditioning and social interactions, while locomotor activity, pre-pulse inhibition and novel object recognition were not impaired. NRG1(+/-) mice had impairments in a subset of behavioral and electrophysiological tasks relevant to the negative/cognitive symptom domains of schizophrenia that are thought to be influenced by glutamatergic and dopaminergic neurotransmission. These mice are a valuable tool for studying endophenotypes of schizophrenia, but highlight that single genes cannot account for the complex pathophysiology of the disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 174 | Mol. Psychiatry 2009 Jun 14: 563-89 |
| PMID | 19204725 |
| Title | Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer. |
| Abstract | Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia. Presumably, owing to etiological complexity identifying susceptibility genes and abnormalities in the development has been difficult. However, the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established. There are 484 annotated genes located on 8p; many are most likely oncogenes and tumor-suppressor genes. Molecular genetics and developmental studies have identified 21 genes in this region (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) that are most likely to contribute to neuropsychiatric disorders (schizophrenia, autism, bipolar disorder and depression), neurodegenerative disorders (Parkinson's and Alzheimer's disease) and cancer. Furthermore, at least seven nonprotein-coding RNAs (microRNAs) are located at 8p. Structural variants on 8p, such as copy number variants, microdeletions or microduplications, might also contribute to autism, schizophrenia and other human diseases including cancer. In this review, we consider the current state of evidence from cytogenetic, linkage, association, gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease. We also describe how a mutation in an 8p gene (Fgf17) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex. We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer, despite the shortcomings of this evidence. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 175 | Acta Neuropsychiatr 2009 Jun 21: 109-20 |
| PMID | 26953749 |
| Title | Schizophrenia: genetics, prevention and rehabilitation. |
| Abstract | Genetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (G×E) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation. Medline search of relevant studies published between 1990 and 2008. In schizophrenia, examples of G×E interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism. This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 176 | Pharmacol. Ther. 2009 Jan 121: 115-22 |
| PMID | 19046988 |
| Title | Altered growth factor signaling pathways as the basis of aberrant stem cell maturation in schizophrenia. |
| Abstract | In recent years evidence has accumulated that the activity of the signaling cascades of Neuregulin-1, Wnt, TGF-beta, BDNF-p75 and DISC1 is different between control subjects and patients with schizophrenia. These pathways are involved in embryonic and adult neurogenesis and neuronal maturation. A review of the clinical data indicates that in schizophrenia the Wnt pathway is most likely hypoactive, whereas the NRG1-ErbB4, the TGF-beta- and the BDNF-p75-pathways are hyperactive. Haplo-insuffiency of the DISC1 gene is currently the best established schizophrenia risk factor. Preclinical experiments indicate that suppression of DISC1 signaling leads to accelerated dendrite development in neuronal stem cells, accelerated migration and aberrant integration into the neuronal network. Other preclinical experiments show that increasing NRG1-, BDNF- and TGF-beta signaling and decreasing Wnt signaling, also promotes adult neuronal differentiation and migration. Thus deviations in these pathways detected in schizophrenia could contribute to premature neuronal differentiation, accelerated migration and inappropriate insertion into the neuronal network. Initial clinical findings are confirmatory: neuronal stem cells isolated from nasal biopsies from schizophrenia patients display signs of accelerated development, whilst increased erosion of telomeres and bone age provide further support for accelerated cell maturation in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 177 | J. Neurogenet. 2009 -1 23: 341-52 |
| PMID | 19225952 |
| Title | Survey of schizophrenia and bipolar disorder candidate genes using chromatin immunoprecipitation and tiled microarrays (ChIP-chip). |
| Abstract | It has been difficult to identify disease-causing alleles in schizophrenia (SZ) and bipolar disorder (BD) candidate genes. One reason is that responsible functional variants may exist in unidentified regulatory domains. With the advent of microarray technology and high throughput sequencing, however, it is now feasible to screen genes for such regulatory domains relatively easily by using chromatin immunoprecipitation-based methodologies, such as ChIP-chip and ChIP-seq. In ChIP-chip, regulatory sequences can be captured from chromatin immunoprecipitates prepared with antibodies against covalently modified histones that mark certain regulatory domains; DNA extracted from such immunoprecipitates can then be used as microarray probes. As a first step toward demonstrating the feasibility of this approach in psychiatric genetics, we used ChIP-chip to identify regulatory domains in several candidate genes: NRG1, DTNBP1, DISC1, DAO, DAOA, PDE4B, and COMT. Immunoprecipitates were generated with antibodies to histone H3 acetylated at lysine 9 (H3K9Ac) and histone H3 monomethylated at lysine 4 (H3K4me1), which mark promoters and some enhancers, using fetal brain chromatin as a substrate. Several novel putative regulatory elements, as well as the core and proximal promoters for each gene, were enriched in the immunoprecipitates. Genetic variants within these regions would be of interest to study as potential disease-associated alleles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 178 | Neurochem. Int. 2009 Dec 55: 606-9 |
| PMID | 19524002 |
| Title | Neuregulin 1-stimulated phosphorylation of AKT in psychotic disorders and its relationship with neurocognitive functions. |
| Abstract | Neuregulin 1 (NRG1) has been implicated in the pathophysiology of psychotic disorders. NRG1 exerts its effects via the Ras-MAPK and phosphatidylinositol-3 kinase-protein kinase B (PI3K-PKB/AKT) intracellular signaling pathways through ErbB receptors. The aim of this study was to investigate the relationship between NRG1-stimulated AKT phosphorylation and neurocognitive functions in patients with schizophrenia and in patients with other psychotic disorders. B lymphoblasts of patients (n=40) and controls (n=20) were stimulated with NRG1a (65 amino-acid residue recombinant protein from the epidermal growth factor [EGF] domain) for 30-min. The protein isolated from the cells was analyzed by Western blotting. The dependent measure was the ratio of phosphorylated AKT (pAKT) and total AKT at baseline (without NRG1 stimulation) and after NRG1 stimulation (pAKT/AKT). The neurocognitive functions (attention, immediate and long-term memory, language, visual-spatial skills) were evaluated by the repeatable brief assessment of neuropsychological status (RBANS) battery. The results revealed a significantly reduced pAKT/AKT ratio in patients with schizophrenia as compared with healthy controls and with patients with other psychotic disorders. The patients with other psychotic disorders did not differ from the healthy controls. Despite the fact that neurocognitive functions were significantly impaired in the patients, these functions did not reveal significant correlations with the pAKT/AKT ratio. In conclusion, NRG1-induced AKT phosphorylation is decreased in schizophrenia but not in other psychotic disorders. This peripheral marker is not related to neurocognitive functions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 179 | J. Biol. Chem. 2009 Jul 284: 18824-32 |
| PMID | 19439407 |
| Title | Transcriptional interaction of an estrogen receptor splice variant and ErbB4 suggests convergence in gene susceptibility pathways in schizophrenia. |
| Abstract | Mounting evidence from clinical and basic research suggests that estrogen signaling may be altered in the brains of people with schizophrenia. Previously, we found that DNA sequence variation in the estrogen receptor (ER) alpha gene, lower ERalpha mRNA levels, and/or blunted ERalpha signaling is associated with schizophrenia. In this study, we asked whether the naturally occurring truncated ERalpha isoform, Delta7, which acts as a dominant negative, can attenuate gene expression induced by the wild-type (WT) receptor in an estrogen-dependent manner in neuronal (SHSY5Y) and non-neuronal (CHOK1 and HeLa) cells. In addition, we determined the extent to which ERalpha interacts with NRG1-ErbB4, a leading schizophrenia susceptibility pathway. Reductions in the transcriptionally active form of ErbB4 comprising the intracytoplasmic domain (ErbB4-ICD) have been found in schizophrenia, and we hypothesized that ERalpha and ErbB4 may converge to control gene expression. In the present study, we show that truncated Delta7-ERalpha attenuates WT-ERalpha-driven gene expression across a wide range of estrogen concentrations in cells that express functional ERalpha at base line or upon co-transfection of full-length ERalpha. Furthermore, we find that ErbB4-ICD can potentiate the transcriptional activity of WT-ERalpha at EREs in two cell lines and that this potentiation effect is abolished by the presence of Delta7-ERalpha. Immunofluorescence microscopy revealed nuclear co-localization of WT-ERalpha, Delta7-ERalpha, and ErbB4-ICD, whereas immunoprecipitation assays showed direct interaction. Our findings demonstrate convergence between ERalpha and ErbB4-ICD in the transcriptional control of ERalpha-target gene expression and suggest that this may represent a convergent pathway that may be disrupted in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 180 | Hum. Mol. Genet. 2009 Feb 18: 391-404 |
| PMID | 18996920 |
| Title | Disrupted-in-schizophrenia 1 and neuregulin 1 are required for the specification of oligodendrocytes and neurones in the zebrafish brain. |
| Abstract | schizophrenia may arise from subtle abnormalities in brain development due to alterations in the functions of candidate susceptibility genes such as Disrupted-in-schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1). To provide novel insights into the functions of DISC1 in brain development, we mapped the expression of zebrafish disc1 and set out to characterize its role in early embryonic development using morpholino antisense methods. These studies revealed a critical requirement for disc1 in oligodendrocyte development by promoting specification of olig2-positive cells in the hindbrain and other brain regions. Since NRG1 has well-documented roles in myelination, we also analyzed the roles of NRG1 and ErbB signalling in zebrafish brain development and we observed strikingly similar defects to those seen in disc1 morphant embryos. In addition to their effects on oligodendrocyte development, knock-down of disc1 or NRG1 caused near total loss of olig2-positive cerebellar neurones, but caused no apparent loss of spinal motor neurones. These findings suggest that disc1 and NRG1 function in common or related pathways controlling development of oligodendrocytes and neurones from olig2-expressing precursor cells. Like DISC1 and NRG1, OLIG2 and ERBB4 are promising candidate susceptibility genes for schizophrenia. Hence our findings in the zebrafish embryo suggest that hitherto unappreciated neurodevelopmental connections may exist between key human schizophrenia susceptibility genes. These connections could be investigated in Disc1 and NRG1 mouse models and in genetically defined groups of patients in order to determine whether they are relevant to the pathobiology of schizophrenia. GenBank accession number for Danio rerio disc1: EU273350. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 181 | Neuropsychopharmacology 2009 Feb 34: 641-50 |
| PMID | 18668031 |
| Title | ErbB4 genotype predicts left frontotemporal structural connectivity in human brain. |
| Abstract | Diminished left frontotemporal connectivity is among the most frequently reported findings in schizophrenia and there is evidence that altered neuronal myelination may in part account for this deficit. Several investigations have suggested that variations of the genes that encode the Neuregulin 1 (NRG1)-ErbB4 receptor complex are associated with schizophrenia illness. As NRG1--ErbB4 has been implicated in neuronal myelination, we investigated with diffusion tensor imaging (DTI) whether fractional anisotropy (FA)--a putative measure of neuronal myelination--is predicted by a risk haplotype of the ErbB4 gene. The effects of the ErbB4 genotype were investigated in healthy subjects (N=59; mean age: 22.6+/-1.8 years). We also measured reaction time (RT) during a selective attention/working memory paradigm (visual oddball). In the schizophrenia risk genotype group, we found lower FA in the temporal lobe white matter (WM) including frontotemporal fiber tracts, predominantly in the left hemisphere. RT was increased in the risk genotype group and correlated with FA in the affected brain region. As FA is considered to index structural integrity of WM, to which neuronal fiber myelination is contributing, our results suggest that variations of the ErbB4 genotype may confer risk for schizophrenia illness via its impact on left frontotemporal connectivity in human brain. Reliability and validity of the result is suggested by our observation that (1) the FA-genotype association was not only obtained in the entire sample but also in both the split halves and (2) a statistical relationship was found among RT, genotype and FA. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 182 | Neuropsychobiology 2009 -1 59: 205-12 |
| PMID | 19521112 |
| Title | Analysis of a promoter polymorphism in the SMDF neuregulin 1 isoform in Schizophrenia. |
| Abstract | Neuregulin 1 (NRG1) is a positional candidate gene in schizophrenia (SZ). Two major susceptibility loci in the NRG1 gene approximately one million nucleotides apart have been identified in genetic studies. Several candidate functional allelic variants have been described that might be involved in disease susceptibility. However, the findings are still preliminary. We recently mapped active promoters and other regulatory domains in several SZ and bipolar disorder (BD) candidate genes using ChIP-chip (chromatin immunoprecipitation hybridized to microarrays). One was the promoter for the NRG1 isoform, SMDF, which maps to the 3' end of the gene complex. Analysis of the SNP database revealed several polymorphisms within the approximate borders of the region immunoprecipitated in our ChIP-chip experiments, one of which is rs7825588. This SNP was analyzed in patients with SZ and BD and its effect on promoter function was assessed by electromobility gel shift assays and luciferase reporter constructs. A significant increase in homozygosity for the minor allele was found in patients with SZ (genotype distribution chi(2) = 7.32, p = 0.03) but not in BD (genotype distribution chi(2) = 0.52, p = 0.77). Molecular studies demonstrated modest, but statistically significant allele-specific differences in protein binding and promoter function. The findings suggest that homozygosity for rs725588 could be a risk genotype for SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 183 | BMC Med Genomics 2009 -1 2: 28 |
| PMID | 19457239 |
| Title | Gene expression in the prefrontal cortex during adolescence: implications for the onset of schizophrenia. |
| Abstract | Many critical maturational processes take place in the human brain during postnatal development. In particular, the prefrontal cortex does not reach maturation until late adolescence and this stage is associated with substantial white matter volume increases. Patients with schizophrenia and other major psychiatric disorders tend to first present with overt symptoms during late adolescence/early adulthood and it has been proposed that this developmental stage represents a "window of vulnerability". In this study we used whole genome microarrays to measure gene expression in post mortem prefrontal cortex tissue from human individuals ranging in age from 0 to 49 years. To identify genes specifically altered in the late adolescent period, we applied a template matching procedure. Genes were identified which showed a significant correlation to a template showing a peak of expression between ages 15 and 25. Approximately 2000 genes displayed an expression pattern that was significantly correlated (positively or negatively) with the template. In the majority of cases, these genes in fact reached a plateau during adolescence with only subtle changes thereafter. These include a number of genes previously associated with schizophrenia including the susceptibility gene neuregulin 1 (NRG1). Functional profiling revealed peak expression in late adolescence for genes associated with energy metabolism and protein and lipid synthesis, together with decreases for genes involved in glutamate and neuropeptide signalling and neuronal development/plasticity. Strikingly, eight myelin-related genes previously found decreased in schizophrenia brain tissue showed a peak in their expression levels in late adolescence, while the single myelin gene reported increased in patients with schizophrenia was decreased in late adolescence. The observed changes imply that molecular mechanisms critical for adolescent brain development are disturbed in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 184 | Hum Brain Mapp 2009 Dec 30: 3934-43 |
| PMID | 19449332 |
| Title | Genetic variation in neuregulin1 is associated with differences in prefrontal engagement in children. |
| Abstract | The majority of psychopathology is rooted early in life and first emerges during childhood and adolescence. However, little is known about how risk genes affect brain function to increase biological vulnerability to psychopathology in childhood, because most imaging genetic studies published so far have been conducted on adult participants. We examined the impact of neuregulin1 (NRG1), a probable susceptibility gene for schizophrenia and bipolar disorder, on brain function in a sample of 102 ten- to twelve-year-old children. Each participant performed a Go/Nogo task, whereas brain responses were measured using functional magnetic resonance imaging. Statistical parametric mapping was used to estimate the impact of genetic variation in NRG1 on brain activation. Response accuracy and reaction times did not differ as a function of NRG1 genotype. However, individuals with the high-risk variant expressed greater brain activation for both Go and Nogo stimuli in the right posterior orbital gyrus, where NRG1 genotype accounted for 11% of interindividual variance. There were no regions showing a significant interaction between NRG1 genotype and stimulus type even at trend level, suggesting that the impact of NRG1 on brain activation was not specific to either response inhibition or motor execution. These results suggest that that genetic variation in NRG1 is associated with different levels of prefrontal engagement in children as young as 10-12 years of age. Our investigation provides support to the idea that genetic factors may affect brain function to moderate vulnerability to psychopathology from childhood. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 185 | J Psychiatry Neurosci 2009 May 34: 181-6 |
| PMID | 19448847 |
| Title | Neuregulin 1 genetic variation and anterior cingulum integrity in patients with schizophrenia and healthy controls. |
| Abstract | Neuregulin1 (NRG1) influences the development of white matter connectivity and is implicated in genetic susceptibility to schizophrenia. The cingulum bundle is a white matter structure implicated in schizophrenia. Its anterior component is especially implicated, as it provides reciprocal connections between brain regions with prominent involvement in the disorder. Abnormalities in the structural integrity of the anterior cingulum in patients with schizophrenia have been reported previously. The present study investigated the potential contribution of NRG1 variation to anterior cingulum abnormalities in participants with schizophrenia. We studied 31 men with schizophrenia and 36 healthy men using diffusion tensor imaging to investigate the association between fractional anisotropy in the anterior cingulum and a single-nucleotide polymorphism (SNP8NRG221533: rs35753505) of NRG1. Consistent with previous reports, fractional anisotropy was significantly reduced in the anterior cingulum in the schizophrenia group. Moreover, the results revealed a significant group (schizophrenia, control) by genotype (C/C, T carriers, including CT and TT) interaction between genetic variation in NRG1 and diagnosis of schizophrenia, such that the patients with the T allele for SNP8NRG221533 had significantly decreased anterior cingulum fractional anisotropy compared with patients homozygous for the C allele and healthy controls who were T carriers. Limitations of our study included the small sample size of the TT subgroup and our use of only fractional anisotropy as an index of myelin integrity. In addition, the use of diffusion tensor imaging acquisition methods limited our ability to study other brain regions that may be involved in schizophrenia. Our results suggest that NRG1 variation may play a role in the pathophysiology of anterior cingulum abnormalities in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 186 | Int. J. Neuropsychopharmacol. 2009 Nov 12: 1383-93 |
| PMID | 19400983 |
| Title | Neuregulin 1 hypomorphic mutant mice: enhanced baseline locomotor activity but normal psychotropic drug-induced hyperlocomotion and prepulse inhibition regulation. |
| Abstract | Neuregulin 1 (NRG1) has been widely recognized as a candidate gene for schizophrenia. This study therefore investigated mice heterozygous for a mutation in the transmembrane domain of this trophic factor (NRG1+/- mice) in a number of behavioural test systems with relevance to schizophrenia, including psychotropic drug-induced locomotor hyperactivity and prepulse inhibition (PPI) of startle. Baseline locomotor activity in the open field or in photocell cages was slightly, but significantly enhanced in NRG1+/- mice compared to wild-type littermate controls at age 12-16 wk, but not at age 6 months. The ability of amphetamine, phencyclidine (PCP) or MK-801 to induce locomotor hyperactivity was not significantly different between the genotypes. There was no difference in baseline PPI, startle or startle habituation and there was no difference in the effect of apomorphine, amphetamine or MK-801 on any of these parameters. Only treatment with the 5-HT1A receptor agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) showed a differential effect between genotypes, with a disruption of PPI occurring in NRG1+/- mice compared to no effect in wild-type controls. This treatment also induced a significant reduction of startle which could have influenced the result. The density of dopamine D2 receptors in the forebrain and of 5-HT1A receptors in the hippocampus and raphe nuclei was not different between NRG1+/- mice and controls. These studies add to the knowledge about behavioural effects in this mouse model of impaired NRG1 function and suggest that a number of the behavioural tests with relevance to schizophrenia are normal in these mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 187 | Schizophr. Res. 2009 Jun 111: 109-14 |
| PMID | 19362450 |
| Title | A two-method meta-analysis of Neuregulin 1(NRG1) association and heterogeneity in schizophrenia. |
| Abstract | NRG1 is one of the most researched genes associated with schizophrenia. Although three meta-analyses in this area have been published, the results have been inconclusive and even conflicting. Family based studies can be problematical due to the difficulty of synthesizing them with case-control studies. Heterogeneity is another persistently difficult problem which tends to be side-stepped in genetic studies. To deal with these points, we performed a meta-analysis of 26 published case-control and family-based association studies up to September 2008 covering 8049 cases, 8869 controls and 1515 families. The matrix of coancestry coefficient was also calculated using population genetics. Across these studies, the conclusions are as follows: Firstly, only SNP8NRG221132, 420M9-1395(0) and 478B14-848(0) showed significant association in the relatively small sample size. Secondly, we applied both Kazeem's and Lohmueller's methods for synthesizing family and case control studies and there was no statistically significant difference between the results from the two methods, suggesting that either method can be used. In addition, the association analysis of case-control studies was statistically consistent with that of family studies. Finally, the matrix of coancestry coefficient suggested obvious population stratification. The study reveals that one SNP of the NRG1 gene does not contribute significantly to schizophrenia and that population stratification is evident. In future genetic association analysis on complex psychic diseases, haplotype blocks and population structure should be given greater consideration. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 188 | Hum Brain Mapp 2009 Oct 30: 3406-16 |
| PMID | 19350564 |
| Title | Genetic variation in the schizophrenia-risk gene neuregulin 1 correlates with brain activation and impaired speech production in a verbal fluency task in healthy individuals. |
| Abstract | Impaired performance in verbal fluency tasks is an often replicated finding in schizophrenia. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal and temporal areas. Since schizophrenia has a high heritability, it is of interest whether susceptibility genes for the disorder, such as NRG1, modulate verbal fluency performance and its neural correlates. Four hundred twenty-nine healthy individuals performed a semantic and a lexical verbal fluency task. A subsample of 85 subjects performed an overt semantic verbal fluency task while brain activation was measured with functional magnetic resonance imaging (MRI). NRG1 (SNP8NRG221533; rs35753505) status was determined and correlated with verbal fluency performance and brain activation. For the behavioral measure, there was a linear effect of NRG1 status on semantic but not on lexical verbal fluency. Performance decreased with number of risk-alleles. In the fMRI experiment, decreased activation in the left inferior frontal and the right middle temporal gyri as well as the anterior cingulate gyrus was correlated with the number of risk-alleles in the semantic verbal fluency task. NRG1 genotype does influence language production on a semantic level in conjunction with the underlying neural systems. These findings are in line with results of studies in schizophrenia and may explain some of the cognitive and brain activation variation found in the disorder. More generally, NRG1 might be one of several genes that influence semantic language capacities. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 189 | Psychiatr. Genet. 2009 Jun 19: 113-6 |
| PMID | 19339916 |
| Title | An association study of the neuregulin 1 gene, bipolar affective disorder and psychosis. |
| Abstract | As evidence of partial aetiological overlap between bipolar affective disorder and schizophrenia is accumulating, it is important to determine whether genes implicated in the aetiology of schizophrenia play a role in bipolar disorder, and vice versa. As the neuregulin 1 (NRG1) gene has been associated with schizophrenia, we set out to investigate whether it is also associated with bipolar affective disorder, using a sample from Scotland, UK. We tested four single nucleotide polymorphisms (SNPs), SNP8NRG221533 (rs35753505), SNP8NRG241930, SNP8NRG243177 (rs6994992) and SNPNRG222662 (rs4623364) for allelic and haplotypic association with bipolar disorder and the presence of psychotic or mood-incongruent psychotic features. We found nominal allele-wise significant association (P = 0.02) for SNP8NRG221533, with the T allele being overrepresented in cases. This is the opposite allelic association to the original association study where the C allele was associated with schizophrenia. Allele-wise significance increased when we tested for association with the subgroups of bipolar disorder with psychotic features (chi2 = 8.53; P = 0.003; odds ratio = 1.49) and, more specifically, with mood-incongruent psychotic features (chi2 = 7.13; P = 0.008; odds ratio = 1.57). Furthermore, both these subphenotypes were significantly associated with the SNP8NRG221533(T)-SNP8NRG241930(G) haplotype (chi2 = 11.94, global P = 0.027 and chi2 = 11.88, global P = 0.019, respectively) and with the SNP8NRG221533(T)-SNP8NRG222662(C)-SNP8NRG241930(G) haplotype (chi2 = 19.98, global P = 0.009) in case of the broader subphenotype of psychotic bipolar. This study supports the hypothesis that NRG1 may play a role in the development of bipolar disorder, especially in psychotic subtypes, albeit with different alleles to previous association reports in schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 190 | Mol. Psychiatry 2009 Aug 14: 786-95 |
| PMID | 19223858 |
| Title | Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms. |
| Abstract | A genomewide linkage scan was carried out in eight clinical samples of informative schizophrenia families. After all quality control checks, the analysis of 707 European-ancestry families included 1615 affected and 1602 unaffected genotyped individuals, and the analysis of all 807 families included 1900 affected and 1839 unaffected individuals. Multipoint linkage analysis with correction for marker-marker linkage disequilibrium was carried out with 5861 single nucleotide polymorphisms (SNPs; Illumina version 4.0 linkage map). Suggestive evidence for linkage (European families) was observed on chromosomes 8p21, 8q24.1, 9q34 and 12q24.1 in nonparametric and/or parametric analyses. In a logistic regression allele-sharing analysis of linkage allowing for intersite heterogeneity, genomewide significant evidence for linkage was observed on chromosome 10p12. Significant heterogeneity was also observed on chromosome 22q11.1. Evidence for linkage across family sets and analyses was most consistent on chromosome 8p21, with a one-LOD support interval that does not include the candidate gene NRG1, suggesting that one or more other susceptibility loci might exist in the region. In this era of genomewide association and deep resequencing studies, consensus linkage regions deserve continued attention, given that linkage signals can be produced by many types of genomic variation, including any combination of multiple common or rare SNPs or copy number variants in a region. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 191 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2009 Feb 26: 16-20 |
| PMID | 19199244 |
| Title | [Association analysis of neuregulin 1 gene polymorphism with schizophrenia in Chinese Han population]. |
| Abstract | To investigate the association of the Neuregulin 1(NRG1) gene polymorphism with schizophrenia by analyzing allele transmission in schizophrenic parent-proband trios. Quantitative real-time PCR was used to check the genotypes of four SNPs-rs221533(C/T), rs7820838(C/T), 433E1006(A/G) and rs3924999(C/T), located at the 5o terminus of the NRG1 gene, in 258 Chinese Han schizophrenic parent-proband trios. The transmission disequilibrium test (TDT) program (Genehunter software 2.0) was used to evaluate the association of the NRG1 gene with schizophrenia. For all the subjects, the genotypes of the 4 SNPs were in Hardy-Weinberg equilibrium. In all the 258 parent-proband trios, there were significant transmission disequilibrium in allelic transmission of C, A, T from rs221533, 433E1006, rs3924999 loci respectively (rs221533: chi-square was 27.45, P was 0.000; 433E1006: chi-square was 56.08, P was 0.000; rs3924999: chi-square was 10.53, P was 0.001). Haplotype was analyzed at frequency exceeding 1%. In three-marker-haplotype, C/C/G and C/C/A (marker order: rs221533, rs7820838, 433E1006) transmitted predominantly(C/C/G: chi-square was 5.26, P was 45.08; C/C/A: chi-square was 0.026, P was 0.000). In four-marker-haplotype (marker order: rs221533, rs7820838, 433E1006, rs3924999), C/C/G/T, C/C/A/C and C/C/A/T showed transmission disequilibrium (C/C/G/T: chi-square was 10.71, P was 0.001; C/C/A/C: chi-square was 8.83, P was 0.006, C/C/A/T: chi-square was 27.00, P was 0.000). In the positive subtype of parent-proband trios, C/T/G/C hapoltype transmission was not observed. The NRG1 gene polymorphism is significantly associated with schizophrenia in Chinese Han, especially in the positive subtype of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 192 | Brain Res. 2009 Mar 1258: 1-11 |
| PMID | 19150438 |
| Title | Differential distribution of neuregulin in human brain and spinal fluid. |
| Abstract | The neuregulins are a family of polypeptide factors implicated in a wide range of neurological and psychiatric disorders including multiple sclerosis, schizophrenia, and Alzheimer's disease. Many alternatively-spliced forms of the NRG1 gene are released as soluble factors that can diffuse to near and distant sites within the nervous system where they can accumulate through binding to highly specific heparan-sulfate proteoglycans in the extracellular matrix. Here we have determined the sites of synthesis and accumulation of heparin-binding neuregulin forms in human neocortex, white matter, cerebral spinal fluid, and serum by immunostaining and measurement of neuregulin activity. While neuregulin precursors are expressed predominately within cortical neurons, soluble neuregulin accumulates preferentially on the surface of white matter astrocytes. Consistently, neuregulin activity can be released from the extracellular matrix of human brain by protease treatment. Neuregulin activity is also detectable in human cerebral spinal fluid where its expression appears to be altered in neuronal disorders. While cerebral spinal fluid neuregulin levels were unaltered in patients with multiple sclerosis, they were slightly reduced in amyotrophic lateral sclerosis and Parkinson's disease (p<0.15), but significantly increased in Alzheimer's disease (p<0.01). While not detected in human serum, a novel neuregulin antagonist activity was identified in human serum that could have prevented its detection. These results suggest that human neuregulin is selectively targeted from cortical neurons to white matter extracellular matrix where it exists in steady-state equilibrium with cerebral spinal fluid where it has the potential to serve as a biological marker in human neuronal disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 193 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Jul 150B: 693-702 |
| PMID | 19127563 |
| Title | Family-based association study of Neuregulin 1 with psychotic bipolar disorder. |
| Abstract | The Neuregulin 1 gene (NRG1) has been associated with schizophrenia, and, to a lesser extent, with bipolar disorder (BP). We investigated the association of NRG1 with BP in a large family sample, and then performed analyses according to the presence of psychotic features or mood-incongruent psychotic features. We genotyped 116 tagSNPs and four Icelandic "core" SNPs in 1,199 subjects from 314 nuclear families. Of 515 BP offspring, 341 had psychotic features, and 103 had mood-incongruent psychotic features. In single-marker and sliding window haplotype analyses using FBAT, there was little association using the standard BP or mood-incongruent psychotic BP phenotypes, but stronger signals were seen in the psychotic BP phenotype. The most significant associations with psychotic BP were in haplotypes within the 5' "core" region. The strongest global P-value was across three SNPs: NRG241930-NRG243177-rs7819063 (P = 0.0016), with an undertransmitted haplotype showing an individual P = 0.0007. The most significant individual haplotype was an undertransmitted two-allele subset of the above (NRG243177-rs7819063, P = 0.0004). Additional associations with psychotic BP were found across six SNPs in a 270 kb central region of the gene. The most 3' of these, rs7005606 (P = 0.0029), is located approximately 4 kb from the type I NRG1 isoform promoter. In sum, our study suggests that NRG1 may be specifically associated with the psychotic subset of BP; however, our results should be interpreted cautiously since they do not meet correction for multiple testing and await independent replication. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 194 | Am. J. Hum. Genet. 2009 Jan 84: 21-34 |
| PMID | 19118813 |
| Title | Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia. |
| Abstract | Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 x 10(-5)), we performed a peakwide association fine mapping study by using 1414 SNPs across approximately 12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the "delusion" factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 x 10(-7). We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 x 10(-2)), with a combined p value of 2.30 x 10(-7). After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 x 10(-3). NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 195 | Biol. Psychiatry 2009 Mar 65: 535-40 |
| PMID | 19058791 |
| Title | A neuregulin 1 variant is associated with increased lateral ventricle volume in patients with first-episode schizophrenia. |
| Abstract | Structural brain abnormalities are already present at early phases of psychosis and might be the consequence of neurodevelopmental deviance. Neuregulin 1 gene (NRG1) is a candidate gene for schizophrenia, and its protein has different roles in nervous system development and plasticity. A single nucleotide polymorphism (SNP) within NRG1, SNP8NRG243177, has been associated with brain function among healthy and high-risk subjects and with reduced cell migration among patients with schizophrenia. We examined whether variations in this polymorphism influence brain volumes in first-episode schizophrenia subjects. Ninety-five minimally medicated patients experiencing their first episode of schizophrenia underwent genotyping of three SNPs within the NRG1 gene and structural brain magnetic resonance imaging (MRI). A comparison of volumes of lobar gray matter (GM), lateral ventricles, and cortical cerebrospinal fluid (CSF) was made between the groups according to their genotype after controlling for total intracranial volume. The SNP8NRG243177 risk T allele was significantly associated, in an allele copy number-dependent fashion, with increased lateral ventricle volume. Genotype explained 7% of the variance of lateral ventricle volume. No significant differences in GM lobar or cortical CSF volumes were found among subgroups. Our findings suggest that genetic variations of the NRG1 gene can contribute to the enlargement of the lateral ventricles described in early phases of schizophrenia. These results suggest novel lines of research into potential mechanisms by which schizophrenia susceptibility genes might exert their effect on brain structure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 196 | Acta Neuropsychiatr 2009 Jun 21: 109-20 |
| PMID | 26953749 |
| Title | Schizophrenia: genetics, prevention and rehabilitation. |
| Abstract | Genetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (G×E) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation. Medline search of relevant studies published between 1990 and 2008. In schizophrenia, examples of G×E interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism. This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 197 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2009 Feb 26: 16-20 |
| PMID | 19199244 |
| Title | [Association analysis of neuregulin 1 gene polymorphism with schizophrenia in Chinese Han population]. |
| Abstract | To investigate the association of the Neuregulin 1(NRG1) gene polymorphism with schizophrenia by analyzing allele transmission in schizophrenic parent-proband trios. Quantitative real-time PCR was used to check the genotypes of four SNPs-rs221533(C/T), rs7820838(C/T), 433E1006(A/G) and rs3924999(C/T), located at the 5o terminus of the NRG1 gene, in 258 Chinese Han schizophrenic parent-proband trios. The transmission disequilibrium test (TDT) program (Genehunter software 2.0) was used to evaluate the association of the NRG1 gene with schizophrenia. For all the subjects, the genotypes of the 4 SNPs were in Hardy-Weinberg equilibrium. In all the 258 parent-proband trios, there were significant transmission disequilibrium in allelic transmission of C, A, T from rs221533, 433E1006, rs3924999 loci respectively (rs221533: chi-square was 27.45, P was 0.000; 433E1006: chi-square was 56.08, P was 0.000; rs3924999: chi-square was 10.53, P was 0.001). Haplotype was analyzed at frequency exceeding 1%. In three-marker-haplotype, C/C/G and C/C/A (marker order: rs221533, rs7820838, 433E1006) transmitted predominantly(C/C/G: chi-square was 5.26, P was 45.08; C/C/A: chi-square was 0.026, P was 0.000). In four-marker-haplotype (marker order: rs221533, rs7820838, 433E1006, rs3924999), C/C/G/T, C/C/A/C and C/C/A/T showed transmission disequilibrium (C/C/G/T: chi-square was 10.71, P was 0.001; C/C/A/C: chi-square was 8.83, P was 0.006, C/C/A/T: chi-square was 27.00, P was 0.000). In the positive subtype of parent-proband trios, C/T/G/C hapoltype transmission was not observed. The NRG1 gene polymorphism is significantly associated with schizophrenia in Chinese Han, especially in the positive subtype of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 198 | Psychiatry Res 2010 Mar 176: 82-4 |
| PMID | 20061032 |
| Title | NRG1 and BDNF genes in schizophrenia: an association study in an Italian case-control sample. |
| Abstract | We tested for associations between five single nucleotide polymorphisms (SNPs) located in the area containing the Neuregulin 1 gene (NRG1) and three SNPs within the brain-derived neutrophic factor gene (BDNF) in an Italian sample consisting of 171 schizophrenia subjects and 349 controls. No association was found for any of the polymorphisms tested, either in single locus or in haplotype analysis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 199 | Brain Res. 2010 Aug 1348: 114-9 |
| PMID | 20561508 |
| Title | Disruption of thermal nociceptive behaviour in mice mutant for the schizophrenia-associated genes NRG1, COMT and DISC1. |
| Abstract | Abnormalities in pain perception, especially altered warmth and heat pain sensitivity, have been reported in schizophrenia. Therefore, genes associated with schizophrenia, including neuregulin-1 (NRG1), catechol-O-methyltranferase (COMT) and disrupted-in-schizophrenia-1 (DISC1), may play a role in modulating the physiological and psychological effects of pain stimuli in such patients. Thermal pain sensitivity was assessed in NRG1, COMT and DISC1 mutant mice, and the anti-nociceptive effects of acute Delta(9)-tetrahydrocannabinol (THC) were compared in NRG1 and COMT mutants. At baseline, deletion of NRG1 and DISC1 each reduced thermal pain sensitivity, while deletion of COMT increased pain sensitivity. Neither NRG1 nor COMT deletion altered the anti-nociceptive effects of acute systemic THC (8.0mg/kg). These results indicate a differential contribution of NRG1 and DISC1 vis-à-vis COMT to the processing of thermal nociceptive stimuli and extend their phenotypic relationship to psychotic illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 200 | J. Biomed. Biotechnol. 2010 -1 2010: 859516 |
| PMID | 20467458 |
| Title | Expressions of neuregulin 1beta and ErbB4 in prefrontal cortex and hippocampus of a rat schizophrenia model induced by chronic MK-801 administration. |
| Abstract | Recent human genetic studies and postmortem brain examinations of schizophrenia patients strongly indicate that dysregulation of NRG1 and ErbB4 may be important pathogenic factors of schizophrenia. However, this hypothesis has not been validated and fully investigated in animal models of schizophrenia. In this study we quantitatively examined NRG1 and ErbB4 protein expressions by immunohistochemistry and Western blot in the brain of a rat schizophrenia model induced by chronic administration of MK-801 (a noncompetitive NMDA receptor antagonist). Our data showed that NRG1beta and ErbB4 expressions were significantly increased in the rat prefrontal cortex and hippocampus but in different subregions. These findings suggest that altered expressions of NRG1 and ErbB4 might be attributed to the schizophrenia. Further study in the role and mechanism of NRG1 and ErbB4 may lead to better understanding of the pathophysiology for this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 201 | Proc. Natl. Acad. Sci. U.S.A. 2010 Jan 107: 1211-6 |
| PMID | 20080551 |
| Title | Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. |
| Abstract | Neuregulin 1 (NRG1) is a trophic factor thought to play a role in neural development. Recent studies suggest that it may regulate neurotransmission, mechanisms of which remain elusive. Here we show that NRG1, via stimulating GABA release from interneurons, inhibits pyramidal neurons in the prefrontal cortex (PFC). Ablation of the NRG1 receptor ErbB4 in parvalbumin (PV)-positive interneurons prevented NRG1 from stimulating GABA release and from inhibiting pyramidal neurons. PV-ErbB4(-/-) mice exhibited schizophrenia-relevant phenotypes similar to those observed in NRG1 or ErbB4 null mutant mice, including hyperactivity, impaired working memory, and deficit in prepulse inhibition (PPI) that was ameliorated by diazepam, a GABA enhancer. These results indicate that NRG1 regulates the activity of pyramidal neurons by promoting GABA release from PV-positive interneurons, identifying a critical function of NRG1 in balancing brain activity. Because both NRG1 and ErbB4 are susceptibility genes of schizophrenia, our study provides insight into potential pathogenic mechanisms of schizophrenia and suggests that PV-ErbB4(-/-) mice may serve as a model in the study of this and relevant brain disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 202 | Behav. Genet. 2010 Mar 40: 157-66 |
| PMID | 19967439 |
| Title | Influence of neuregulin1 genotype on neural substrate of perceptual matching in children. |
| Abstract | Adult psychopathology is often rooted early in life and first emerges during childhood and adolescence. However, as most imaging genetic research to date has involved adult participants, little is known about how risk genes affect brain function to influence biological vulnerability in childhood. We examined the impact of neuregulin1 (NRG1), a probable susceptibility gene for schizophrenia and bipolar disorder, on brain function in a sample of 102 healthy 10-12 year old boys including 18 pairs of monozygotic twins, 24 pairs of dizygotic twins and 18 singletons. Each participant performed a perceptual matching task, while brain responses were measured using functional magnetic resonance imaging. Response accuracy and reaction times did not differ as a function of NRG1 genotype; however, individuals with two high-risk alleles showed relatively increased brain activation in a distributed network comprising the precuneus bilaterally, and the left cuneus, middle occipital gyrus, angular gyrus and caudate nucleus. These results indicate that genetic variation in NRG1 significantly affects cortical function during perceptual and monitoring processes in healthy children as young as 10-12 years of age. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 203 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Jan 153B: 141-7 |
| PMID | 19367584 |
| Title | NRG1 gene in recurrent major depression: no association in a large-scale case-control association study. |
| Abstract | The Neuregulin 1 (NRG1) gene was initially implicated in schizophrenia (SZ) and has recently been associated with bipolar disorder (BPD) in two studies. An association with major depressive disorder (MDD) has not yet been investigated but is warranted in view of the genetic overlap between MDD and BPD. We have performed a large-scale case-control study investigating the association between NRG1 polymorphisms and MDD, genotyping a selection of 14 single nucleotide polymorphisms (SNPs) spanning the NRG1 gene in a sample of 1,398 patients of White European ancestry with a diagnosis of MDD and 1,304 ethnically matched controls from three clinical sites in the UK. We found no single marker or haplotype associations that withstood correction for multiple testing. Our findings do not provide evidence that NRG1 plays a role in MDD or that this gene explains part of the genetic overlap with BPD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 204 | Arch. Gen. Psychiatry 2010 Oct 67: 991-1001 |
| PMID | 20921115 |
| Title | Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls. |
| Abstract | NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. schizophrenia is a complex disorder, with etiology likely due to epistasis. To examine epistasis between NRG1 and selected N-methyl-d-aspartate-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, and NOS1AP. schizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls. A referred sample of schizophrenic patients (n = 296) meeting DSM-IV criteria for schizophrenia spectrum disorder and a volunteer sample of controls for case-control comparison (n = 365) and a separate volunteer sample of controls for neuroimaging (n = 172). Epistatic association between single-nucleotide polymorphisms (SNPs) and case-control status; epistatic association between SNPs and the blood oxygen level-dependent physiological response during working memory measured by functional magnetic resonance imaging. We observed interaction between NRG1 5' and 3' SNPs rs4560751 and rs3802160 (likelihood ratio test P = .00020) and schizophrenia, which was validated using functional magnetic resonance imaging of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in the dorsolateral prefrontal cortex (P = .015, familywise error corrected). We observed epistasis between NRG1 (rs10503929; Thr286/289/294Met) and its receptor ERBB4 (rs1026882; likelihood ratio test P = .035); a 3-way interaction with these 2 SNPs and AKT1 (rs2494734) was also observed (odds ratio, 27.13; 95% confidence interval, 3.30-223.03; likelihood ratio test P = .042). These same 2- and 3-way interactions were further biologically validated via functional magnetic resonance imaging: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these 2 together with AKT1, were disproportionately less efficient in dorsolateral prefrontal cortex processing. Lower-level interactions were not observed between NRG1 /ERBB4 and AKT1 in association or neuroimaging, consistent with biological evidence that NRG1 × ERBB4 interaction modulates downstream AKT1 signaling. Our data suggest complex epistatic effects implicating an NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 205 | PLoS ONE 2010 -1 5: e10789 |
| PMID | 20520724 |
| Title | Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models. |
| Abstract | Neuregulin1 (NRG1)-ErbB signaling has been implicated in the pathogenesis of cancer and schizophrenia. We have previously reported that NRG1-stimulated migration of B lymphoblasts is PI3K-AKT1dependent and impaired in patients with schizophrenia and significantly linked to the catechol-o-methyltransferase (COMT) Val108/158Met functional polymorphism. We have now examined AKT1 activation in NRG1-stimulated B lymphoblasts and other cell models and explored a functional relationship between COMT and AKT1. NRG1-induced AKT1 phosphorylation was significantly diminished in Val carriers compared to Met carriers in both normal subjects and in patients. Further, there was a significant epistatic interaction between a putatively functional coding SNP in AKT1 (rs1130233) and COMT Val108/158Met genotype on AKT1 phosphorylation. NRG1 induced translocation of AKT1 to the plasma membrane also was impaired in Val carriers, while PIP(3) levels were not decreased. Interestingly, the level of COMT enzyme activity was inversely correlated with the cells' ability to synthesize phosphatidylserine (PS), a factor that attracts the pleckstrin homology domain (PHD) of AKT1 to the cell membrane. Transfection of SH-SY5Y cells with a COMT Val construct increased COMT activity and significantly decreased PS levels as well as NRG1-induced AKT1 phosphorylation and migration. Administration of S-adenosylmethionine (SAM) rescued all of these deficits. These data suggest that AKT1 function is influenced by COMT enzyme activity through competition with PS synthesis for SAM, which in turn dictates AKT1-dependent cellular responses to NRG1-mediated signaling. Our findings implicate genetic and functional interactions between COMT and AKT1 and may provide novel insights into pathogenesis of schizophrenia and other ErbB-associated human diseases such as cancer. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 206 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Oct 34: 1259-65 |
| PMID | 20638435 |
| Title | An exploratory model for G x E interaction on hippocampal volume in schizophrenia; obstetric complications and hypoxia-related genes. |
| Abstract | Smaller hippocampal volume has repeatedly been reported in schizophrenia patients. Obstetric complications (OCs) and single nucleotide polymorphism (SNP) variation in schizophrenia susceptibility genes have independently been related to hippocampal volume. We investigated putative independent and interaction effects of severe hypoxia-related OCs and variation in four hypoxia-regulated schizophrenia susceptibility genes (BDNF, DTNBP1, GRM3 and NRG1) on hippocampal volume in schizophrenia patients and healthy controls. Clinical assessment, structural MRI scans, and blood samples for genotyping of 32 SNPs were obtained from 54 schizophrenia patients and 53 control subjects. Information on obstetric complications was collected from original birth records. Severe OCs were related to hippocampal volume in both patients with schizophrenia and healthy control subjects. Of the 32 SNPs studied, effects of severe OCs on hippocampal volume were associated with allele variation in GRM3 rs13242038, but the interaction effect was not specific for schizophrenia. SNP variation in any of the four investigated genes alone did not significantly affect hippocampal volume. The findings suggest a gene-environment (G x E) interaction between GRM3 gene variants and severe obstetric complications on hippocampus volume, independent of a diagnosis of schizophrenia. Due to the modest sample size, the results must be considered preliminary and require replication in independent samples. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 207 | Proc. Natl. Acad. Sci. U.S.A. 2010 Dec 107: 21818-23 |
| PMID | 21106764 |
| Title | ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation. |
| Abstract | Neuregulin 1 (NRG1) is a trophic factor that acts by stimulating ErbB receptor tyrosine kinases and has been implicated in neural development and synaptic plasticity. In this study, we investigated mechanisms of its suppression of long-term potentiation (LTP) in the hippocampus. We found that NRG1 did not alter glutamatergic transmission at SC-CA1 synapses but increased the GABA(A) receptor-mediated synaptic currents in CA1 pyramidal cells via a presynaptic mechanism. Inhibition of GABA(A) receptors blocked the suppressing effect of NRG1 on LTP and prevented ecto-ErbB4 from enhancing LTP, implicating a role of GABAergic transmission. To test this hypothesis further, we generated parvalbumin (PV)-Cre;ErbB4(-/-) mice in which ErbB4, an NRG1 receptor in the brain, is ablated specifically in PV-positive interneurons. NRG1 was no longer able to increase inhibitory postsynaptic currents and to suppress LTP in PV-Cre;ErbB4(-/-) hippocampus. Accordingly, contextual fear conditioning, a hippocampus-dependent test, was impaired in PV-Cre;ErbB4(-/-) mice. In contrast, ablation of ErbB4 in pyramidal neurons had no effect on NRG1 regulation of hippocampal LTP or contextual fear conditioning. These results demonstrate a critical role of ErbB4 in PV-positive interneurons but not in pyramidal neurons in synaptic plasticity and support a working model that NRG1 suppresses LTP by enhancing GABA release. Considering that NRG1 and ErbB4 are susceptibility genes of schizophrenia, these observations contribute to a better understanding of how abnormal NRG1/ErbB4 signaling may be involved in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 208 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Dec 34: 1375-80 |
| PMID | 20600464 |
| Title | Genetic findings in schizophrenia patients related to alterations in the intracellular Ca-homeostasis. |
| Abstract | There is a relatively high genetic heritability of schizophrenia as shown by family, twin and adoption studies. A large number of hypotheses on the causes of schizophrenia occurred over time. In this review we focus on genetic findings related to potential alterations of intracellular Ca-homeostasis in association with schizophrenia. First, we provide evidence for the NMDA/glutamatergic theory of schizophrenia including calcium processes. We mainly focus on genes including: DAO (D-amino acid oxidase), DAOA (D-amino acid oxidase activator), DTNBP1 (Dysbindin 1, dystrobrevin-binding protein 1), NRG1 (Neuregulin 1), ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4, avian), NOS1 (nitric oxide synthase 1, neuronal) and NRGN (Neurogranin). Furthermore, a gene coding for a calcium channel subunit (CACNA1C: calcium channel, voltage-dependent, L type, alpha 1C subunit) is discussed in the light of schizophrenia whereas genetic findings related to alterations in the intracellular Ca-homeostasis associated specifically with dopaminergic and serotonergic neurotransmission in schizophrenia are not herein closer reviewed. Taken together there is converging evidence for the contribution of genes potentially related to alterations in intracellular Ca-homeostasis to the risk of schizophrenia. Replications and functional studies will hopefully provide further insight into these genetic variants and the underlying processes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 209 | Schizophr. Res. 2010 Dec 124: 200-7 |
| PMID | 20926259 |
| Title | Decreased Neuregulin 1 C-terminal fragment in Brodmann's area 6 of patients with schizophrenia. |
| Abstract | Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. A decrease in NRG1-ErbB4 signalling has also been associated with the disease. ?-amyloid precursor protein-cleaving enzyme (BACE1) processes type III NRG1 precursor, a major neuregulin variant expressed in the brain, to release NRG1 fragments that trigger signalling events and activation of neurotransmitter receptors. Experimental evidence suggests that muscarinic acetylcholine receptors (CHRM) regulate BACE1 expression. Having recently shown that CHRM1 levels are decreased selectively in frontal cortex regions of a subpopulation of schizophrenic patients (muscarinic receptor deficit schizophrenia, MRDS) we aimed to compare the protein expression of BACE1 and NRG1 in the agranular frontal cortex Brodmann's area 6 of SCZ subjects with normal levels of CHRM1 (N = 19), MRDS (N = 20), and age/gender-matched non-psychiatric (healthy) controls (HC; N = 20). Western blot analysis of post-mortem samples showed that the levels of BACE1 and full-length NRG1 precursor (130 kDa) did not differ significantly between the three groups. In contrast, the levels of the NRG1 C-terminal fragment (NRG1-CTF) were decreased by approximately 50% in both schizophrenic groups compared to the HC group (p<0.0027). The ratio of NRG1-CTF versus NRG1 precursor was significantly reduced in the SCZ groups compared to the HC group (p = 0.051). There was no correlation between the levels of either full-length NRG1, NRG1-CTF, or BACE1 and the final recorded doses of antipsychotic drugs for the subjects with schizophrenia. A positive correlation was found between BACE1 and full-length NRG1 precursor in the HC group (r(2) = 0.671, p<0.001) but not in the schizophrenic groups. These data suggest that the proteolytic processing of NRG1 is impaired in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 210 | Proc. Natl. Acad. Sci. U.S.A. 2010 Aug 107: 15619-24 |
| PMID | 20713722 |
| Title | Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain. |
| Abstract | Structural and polymorphic variations in Neuregulin 3 (NRG3), 10q22-23 are associated with a broad spectrum of neurodevelopmental disorders including developmental delay, cognitive impairment, autism, and schizophrenia. NRG3 is a member of the neuregulin family of EGF proteins and a ligand for the ErbB4 receptor tyrosine kinase that plays pleotropic roles in neurodevelopment. Several genes in the NRG-ErbB signaling pathway including NRG1 and ErbB4 have been implicated in genetic predisposition to schizophrenia. Previous fine mapping of the 10q22-23 locus in schizophrenia identified genome-wide significant association between delusion severity and polymorphisms in intron 1 of NRG3 (rs10883866, rs10748842, and rs6584400). The biological mechanisms remain unknown. We identified significant association of these SNPs with increased risk for schizophrenia in 350 families with an affected offspring and confirmed association to patient delusion and positive symptom severity. Molecular cloning and cDNA sequencing in human brain revealed that NRG3 undergoes complex splicing, giving rise to multiple structurally distinct isoforms. RNA expression profiling of these isoforms in the prefrontal cortex of 400 individuals revealed that NRG3 expression is developmentally regulated and pathologically increased in schizophrenia. Moreover, we show that rs10748842 lies within a DNA ultraconserved element and homedomain and strongly predicts brain expression of NRG3 isoforms that contain a unique developmentally regulated 5' exon (P = 1.097E(-12) to 1.445E(-15)). Our observations strengthen the evidence that NRG3 is a schizophrenia susceptibility gene, provide quantitative insight into NRG3 transcription traits in the human brain, and reveal a probable mechanistic basis for disease association. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 211 | Neurochem. Int. 2010 Jul 56: 906-10 |
| PMID | 20371257 |
| Title | Neuregulin 1-induced AKT phosphorylation in monozygotic twins discordant for schizophrenia. |
| Abstract | Patients with schizophrenia exhibit decreased neuregulin 1 (NRG1)-stimulated AKT phosphorylation in peripheral lymphoblasts. Here, we examined this peripheral marker in monozygotic twins discordant for schizophrenia and in healthy monozygotic twins without psychiatric disorders. B lymphoblasts were stimulated with NRG1a (65 amino-acid residue recombinant protein from the epidermal growth factor [EGF] domain) for 30min. The protein isolated from the cells was analysed by Western blotting. The dependent measure was the ratio of phosphorylated AKT (pAKT) and total AKT at baseline (without NRG1 stimulation) and after NRG1 stimulation (pAKT/AKT). The results revealed that in the case of the unaffected co-twins of patients with schizophrenia, NRG1-stimulated pAKT/AKT ratio was in between the values of their co-twins with schizophrenia and that of the healthy control twin pairs. When the affected twins with schizophrenia were compared with their unaffected co-twins using a Mann-Whitney U-test, we found significantly lower NRG1-induced pAKT/AKT ratios in the patients relative to their unaffected co-twins (p=0.004). However, using a more conservative analysis (Kruskal-Wallis ANOVA followed tests for multiple comparisons), this difference was not significant. The unaffected co-twins of patients with schizophrenia did not differ significantly from the healthy control twins. In the baseline condition, the pAKT/AKT ratios were similar in all groups. These results indicate that impaired AKT-related intracellular signaling is partly related to the developed illness and cannot fully be explained by the genetic background of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 212 | Biosci. Rep. 2010 Aug 30: 267-75 |
| PMID | 19681757 |
| Title | In silico analysis of neuregulin 1 evolution in vertebrates. |
| Abstract | NRG1 (neuregulin 1) belongs to the NRG family of EGF (epidermal growth factor)-like signalling molecules involved in cell-cell communication during development and disease. It plays important roles in the developing tissues of the nerves, heart and mammary glands. Particularly in neurobiology, NRG1 signalling is associated with synaptic transmission, myelination of Schwann cells and the human disease of schizophrenia. Many different isoforms of NRG1 make the molecule highly sophisticated in biological activities and a great diversity of in vivo functions. The nervous system is a common trait in all bilateria (higher animals), but based on the BLAST information from the currently available databases it appears that NRG1 orthologues can only be identified in vertebrates. The gene was analysed in silico for type I-IV CDSs (coding sequences) from ten vertebrate genomes. The gene loci, structures of coding-intronic sequences, ClustalW program analyses, phylogenetic trees and conserved motifs in ecto- and cyto-plasmic domains were analysed and compared. Here, we conclude that non-mammalian vertebrates mainly carry type I (may have evolved a spacer different from mammalian isoforms), II and III NRG1s. The type IV NRG1 N-terminal CDSs can be identified from most of the mammalian genomes studied; however, the corresponding rodent sequences lack the start codon. The evolutionary conservation of a CDS59-CDS24-CDS103 domain, intracellular phosphorylation sites and bipartite nuclear localization signals is of physiological significance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 213 | Proc. Natl. Acad. Sci. U.S.A. 2010 Mar 107: 5622-7 |
| PMID | 20212127 |
| Title | Disrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade. |
| Abstract | Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia-1 (DISC1) are promising susceptibility factors for schizophrenia. Both are multifunctional proteins with roles in a variety of neurodevelopmental processes, including progenitor cell proliferation, migration, and differentiation. Here, we provide evidence linking these factors together in a single pathway, which is mediated by ErbB receptors and PI3K/Akt. We show that signaling by NRG1 and NRG2, but not NRG3, increase expression of an isoform of DISC1 in vitro. Receptors ErbB2 and ErbB3, but not ErbB4, are responsible for transducing this effect, and PI3K/Akt signaling is also required. In NRG1 knockout mice, this DISC1 isoform is selectively reduced during neurodevelopment. Furthermore, a similar decrease in DISC1 expression is seen in beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) knockout mice, in which NRG1/Akt signaling is reportedly impaired. In contrast to neuronal DISC1 that was reported and characterized, expression of DISC1 in other types of cells in the brain has not been addressed. Here we demonstrate that DISC1, like NRG and ErbB proteins, is expressed in neurons, astrocytes, oligodendrocytes, microglia, and radial progenitors. These findings may connect NRG1, ErbBs, Akt, and DISC1 in a common pathway, which may regulate neurodevelopment and contribute to susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 214 | Brain Res. Bull. 2010 Sep 83: 122-31 |
| PMID | 20688137 |
| Title | The neuregulin signaling pathway and schizophrenia: from genes to synapses and neural circuits. |
| Abstract | Numerous genetic linkage and association studies implicate members of the Neuregulin-ErbB receptor (NRG-ErbB) signaling pathway as schizophrenia "at risk" genes. An emphasis of this review is to propose plausible neurobiological mechanisms, regulated by the Neuregulin-ErbB signaling network, that may be altered in schizophrenia and contribute to its etiology. To this end, the distinct neurotransmitter pathways, neuronal subtypes and neural network systems altered in schizophrenia are initially discussed. Next, the review focuses on the possible significance of genetic studies associating NRG1 and ErbB4 with schizophrenia, in light of the functional role of this signaling pathway in regulating glutamatergic, GABAergic and dopaminergic neurotransmission, as well as modulating synaptic plasticity and gamma oscillations. The importance of restricted ErbB4 receptor expression in GABAergic interneurons is emphasized, particularly their expression at glutamatergic synapses of parvalbumin-positive fast-spiking interneurons where modulation of inhibitory drive could account for the dramatic effects of NRG-ErbB signaling on gamma oscillations and pyramidal neuron output. A case is made for reasons that the NRG-ErbB signaling pathway constitutes a "biologically plausible" system for understanding the pathogenic mechanisms that may underlie the complex array of positive, negative and cognitive deficits associated with schizophrenia during development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 215 | Brain Res. Bull. 2010 Sep 83: 132-9 |
| PMID | 20433909 |
| Title | Neuregulin 1-erbB4 pathway in schizophrenia: From genes to an interactome. |
| Abstract | Recently identified candidate susceptibility genes for schizophrenia are likely to play, important roles in the pathophysiology of the illness. It is also clear, however, that the etiologic, contribution of these genes is not only via their own functions but also through interactions with other, genes and environmental factors. Genetic, transgenic and postmortem brain studies support a, potential role for NRG1-erbB4 signaling in schizophrenia. Embedded in the results of these studies, however, are clues to the notion that NRG1-erbB4 signaling does not act alone but in conjunction with, other pathways. This article aims to re-evaluate the evidence for the role of neuregulin 1 (NRG1)-erbB4 signaling in schizophrenia by focusing on its interactions with other candidate susceptibility, pathways. In addition, we consider molecular substrates upon which the NRG1-erbB4 and other, candidate pathways converge contributing to susceptibility for the illness (schizophrenia interactome). Glutamatergic signaling can be an interesting candidate for schizophrenia interactome. schizophrenia is associated with NMDA receptor hypofunction and moreover, several susceptibility genes for, schizophrenia converge on NMDA receptor signaling. These candidate genes influence NMDA receptor, signaling via diverse mechanisms, yet all eventually impact on protein composition of NMDA receptor, complexes. Likewise, the protein associations in the receptor complexes can themselves modulate, signaling molecules of candidate genes and their pathways. Therefore, protein-protein interactions in the NMDA receptor complexes can mediate reciprocal interactions between NMDA receptor function, and susceptibility candidate pathways including NRG1-erbB4 signaling and thus can be a, schizophrenia interactome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 216 | Nature 2010 Apr 464: 1376-80 |
| PMID | 20393464 |
| Title | Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. |
| Abstract | schizophrenia is a complex disorder that interferes with the function of several brain systems required for cognition and normal social behaviour. Although the most notable clinical aspects of the disease only become apparent during late adolescence or early adulthood, many lines of evidence suggest that schizophrenia is a neurodevelopmental disorder with a strong genetic component. Several independent studies have identified neuregulin 1 (NRG1) and its receptor ERBB4 as important risk genes for schizophrenia, although their precise role in the disease process remains unknown. Here we show that NRG1 and ErbB4 signalling controls the development of inhibitory circuitries in the mammalian cerebral cortex by cell-autonomously regulating the connectivity of specific GABA (gamma-aminobutyric acid)-containing interneurons. In contrast to the prevalent view, which supports a role for these genes in the formation and function of excitatory synapses between pyramidal cells, we found that ErbB4 expression in the mouse neocortex and hippocampus is largely confined to certain classes of interneurons. In particular, ErbB4 is expressed by many parvalbumin-expressing chandelier and basket cells, where it localizes to axon terminals and postsynaptic densities receiving glutamatergic input. Gain- and loss-of-function experiments, both in vitro and in vivo, demonstrate that ErbB4 cell-autonomously promotes the formation of axo-axonic inhibitory synapses over pyramidal cells, and that this function is probably mediated by NRG1. In addition, ErbB4 expression in GABA-containing interneurons regulates the formation of excitatory synapses onto the dendrites of these cells. By contrast, ErbB4 is dispensable for excitatory transmission between pyramidal neurons. Altogether, our results indicate that NRG1 and ErbB4 signalling is required for the wiring of GABA-mediated circuits in the postnatal cortex, providing a new perspective to the involvement of these genes in the aetiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 217 | PLoS ONE 2010 -1 5: e14185 |
| PMID | 21151609 |
| Title | Phenotypic characterization of transgenic mice overexpressing neuregulin-1. |
| Abstract | Neuregulin-1 (NRG1) is one of the susceptibility genes for schizophrenia and implicated in the neurotrophic regulation of GABAergic and dopaminergic neurons, myelination, and NMDA receptor function. Postmortem studies often indicate a pathologic association of increased NRG1 expression or signaling with this illness. However, the psychobehavioral implication of NRG1 signaling has mainly been investigated using hypomorphic mutant mice for individual NRG1 splice variants. To assess the behavioral impact of hyper NRG1 signaling, we generated and analyzed two independent mouse transgenic (Tg) lines carrying the transgene of green fluorescent protein (GFP)-tagged type-1 NRG1 cDNA. The promoter of elongation-factor 1? gene drove ubiquitous expression of GFP-tagged NRG1 in the whole brain. As compared to control littermates, both heterozygous NRG1-Tg lines showed increased locomotor activity, a nonsignificant trend toward decreasing prepulse inhibition, and decreased context-dependent fear learning but exhibited normal levels of tone-dependent learning. In addition, social interaction scores in both Tg lines were reduced in an isolation-induced resident-intruder test. There were also phenotypic increases in a GABAergic marker (parvalbumin) as well as in myelination markers (myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase) in their frontal cortex, indicating the authenticity of NRG1 hyper-signaling, although there were marked decreases in tyrosine hydroxylase levels and dopamine content in the hippocampus. These findings suggest that aberrant hyper-signals of NRG1 also disrupt various cognitive and behavioral processes. Thus, neuropathological implication of hyper NRG1 signaling in psychiatric diseases should be evaluated with further experimentation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 218 | Neuroscience 2010 Oct 170: 800-7 |
| PMID | 20678553 |
| Title | Cognition in transmembrane domain neuregulin 1 mutant mice. |
| Abstract | Neuregulin 1 (NRG1), which has been implicated in the development of schizophrenia, is expressed widely throughout the brain and influences key neurodevelopmental processes such as myelination and neuronal migration. The heterozygous transmembrane domain NRG1 mutant mouse (NRG1 TM HET) exhibits a neurobehavioural phenotype relevant for schizophrenia research, characterized by the development of locomotor hyperactivity, social withdrawal, increased sensitivity to environmental manipulation, and changes to the serotonergic system. As only limited data are available on the learning and memory performance of NRG1 TM HET mice, we conducted a comprehensive examination of these mice and their wild type-like littermates in a variety of paradigms, including fear conditioning (FC), radial arm maze (RAM), Y maze, object exploration and passive avoidance (PA). Male neuregulin 1 hypomorphic mice displayed impairments in the novel object recognition and FC tasks, including reduced interest in the novel object and reduced FC to a context, but not a discrete cue. These cognitive deficits were task-specific, as no differences were seen between mutant and control mice in spatial learning (i.e. RAM and Y maze) for both working and reference memory measures, or in the PA paradigm. These findings indicate that neuregulin 1 plays a moderate role in cognition and present further behavioural validation of this genetic mouse model for the schizophrenia candidate gene neuregulin 1. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 219 | J. Mol. Med. 2010 Nov 88: 1133-41 |
| PMID | 20625696 |
| Title | In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation. |
| Abstract | Neuregulin 1 (NRG1) has been implicated in several disorders including breast cancer, multiple sclerosis, and schizophrenia. Also, recent evidence suggests that NRG1 may play a role in regulation of inflammation and immune system response. We therefore hypothesized that a schizophrenia-associated missense mutation (valine to leucine) we identified within the transmembrane region of NRG1 would also be linked to immune dysregulation. We used plasma samples from families carrying the mutation to measure levels of antibodies to 41 autoimmune markers and six cytokines (IL-1b, IL-6, IL-10, IL-8, IL-12p70, and TNF-?) and used these levels as quantitative traits to evaluate association with the NRG1 mutation, using FBAT. Next, we used Epstein-Barr virus-transformed B cells from heterozygous mutation carriers and wild-type individuals to evaluate protein and mRNA cytokine expression in vitro using quantitative PCR and ELISA assays. In vivo, increased levels of 25 autoimmune markers as well as elevated levels of cytokines were significantly associated with the NRG1 mutation. In vitro, we observed a significant increase in protein secretion levels of IL-6, TNF-?, and IL-8 in mutation carriers compared with controls. At the mRNA level, we observed a significant increase in IL-6 expression, while IL-4 levels appeared to be down-regulated in heterozygous individuals compared with wild-type controls. This is the first report of association of a NRG1 mutation with immune dysregulation. This study could contribute towards understanding the role of NRG1 in the pathogenesis of schizophrenia and other disorders in which inflammation plays an important role. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 220 | J. Neurosci. 2010 Jul 30: 9199-208 |
| PMID | 20610754 |
| Title | Intramembranous valine linked to schizophrenia is required for neuregulin 1 regulation of the morphological development of cortical neurons. |
| Abstract | Neuregulin 1 (NRG1) signaling is critical to various aspects of neuronal development and function. Among different NRG1 isoforms, the type III isoforms of NRG1 are unique in their ability to signal via the intracellular domain after gamma-secretase-dependent intramembranous processing. However, the functional consequences of type III NRG1 signaling via its intracellular domain are mostly unknown. In this study, we have identified mutations within type III NRG1 that disrupt intramembranous proteolytic processing and abolish intracellular domain signaling. In particular, substitutions at valine 321, previously linked to schizophrenia risks, result in NRG1 proteins that fail to undergo gamma-secretase-mediated nuclear localization and transcriptional activation. Using processing-defective mutants of type III NRG1, we demonstrate that the intracellular domain signaling is specifically required for NRG1 regulation of the growth and branching of cortical dendrites but not axons. Consistent with the role of type III NRG1 signaling via the intracellular domain in the initial patterning of cortical dendrites, our findings from pharmacological and genetic studies indicate that type III NRG1 functions in dendritic development independent of ERBB kinase activity. Together, these results support the proposal that aberrant intramembranous processing and defective signaling via the intracellular domain of type III NRG1 impair a subset of NRG1 functions in cortical development and contribute to abnormal neuroconnectivity implicated in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 221 | Psychopharmacology (Berl.) 2010 Aug 211: 277-89 |
| PMID | 20571781 |
| Title | A follow-up study: acute behavioural effects of Delta(9)-THC in female heterozygous neuregulin 1 transmembrane domain mutant mice. |
| Abstract | Heavy cannabis use is linked with an increased risk for schizophrenia. We showed previously that male heterozygous neuregulin 1 transmembrane domain (NRG1 HET) mice are more sensitive to some effects of the psychotropic cannabis constituent Delta(9)-tetrahydrocannabinol (THC). We report data from a follow-up study in female NRG1 HET mice, investigating THC effects on behaviours with some relevance to schizophrenia. Mice were injected with THC (0, 5 or 10 mg/kg i.p.) 30 min before a test battery: open field, elevated plus maze, novel object recognition (set 1) or light-dark, social interaction (SI) and prepulse inhibition (PPI 1: variable interstimulus interval (ISI); set 2). Another set (set 3) was injected with the same doses of THC before a fixed interstimulus interval PPI test (PPI 2). Female NRG1 HETs displayed the hallmark increased locomotor activity at 5 months and anxiolytic-like behaviour in the open field at 3 and 5 months. THC decreased locomotor activity in both genotypes. THC selectively reduced some SI behaviours in WT mice. Baseline PPI was enhanced in mutants under a variable ISI, while THC had no effect on PPI using either protocol. This study reports novel findings on the baseline PPI profile and resistance to THC-induced social withdrawal in female NRG1 HET mice. This is the first description of THC effects in females of this mouse model and suggests that the transmembrane domain NRG1 mutation does not appear to have a severe impact on the behavioural sensitivity to THC in female mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 222 | J Neural Transm (Vienna) 2010 Jul 117: 887-95 |
| PMID | 20526724 |
| Title | Measurement and comparison of serum neuregulin 1 immunoreactivity in control subjects and patients with schizophrenia: an influence of its genetic polymorphism. |
| Abstract | Neuregulin-1 (NRG1) gene is implicated in the etiology or neuropathology of schizophrenia, although its biological contribution to this illness is not fully understood. We have established an enzyme-linked immunosorbent assay (ELISA), which recognizes the NRG1beta1 immunoglobulin-like (Ig) domain, and measured soluble Ig-NRG1 immunoreactivity in the sera of chronic schizophrenia patients (n = 40) and healthy volunteers (n = 59). ELISA detected remarkably high concentrations of Ig-NRG1 immunoreactivity in human serum (mean 5.97 +/- 0.40 ng/mL, ~213 +/- 14 pM). Gender and diagnosis exhibited significant effects on serum Ig-NRG1 immunoreactivity. Mean Ig-NRG1 immunoreactivity in the schizophrenia group was 63.2% of that measured in the control group. Ig-NRG1 immunoreactivity in women was 147.1% of that seen in men. We also attempted to correlate six SNPs of NRG1 genome with serum Ig-NRG1 immunoreactivity. Analysis of covariance with compensation for gender identified a significant interaction between diagnosis and SNP8NRG243177 allele. The T allele of this SNP significantly contributed to the disease-associated decrease in Ig-NRG1 immunoreactivity. Although we hypothesized a chronic influence of antipsychotic medications, there was no significant effect of chronic haloperidol treatment on serum Ig-NRG1 immunoreactivity in monkeys. These findings suggest that serum NRG1 levels are decreased in patients with chronic schizophrenia and influenced by their SNP8NRG243177 alleles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 223 | Genes Brain Behav. 2010 Aug 9: 621-7 |
| PMID | 20497232 |
| Title | Association of Neuregulin 1 rs3924999 genotype with antisaccades and smooth pursuit eye movements. |
| Abstract | Neuregulin 1 (NRG1) has been identified as one of the leading candidate genes for schizophrenia. However, its functional mechanisms and its effects on neurocognition remain unclear. In this study, we used two well-established oculomotor endophenotypes, the antisaccade (AS) and smooth pursuit eye movement (SPEM) tasks, to investigate the functional mechanisms of a single nucleotide polymorphism (SNP) in NRG1 (rs3924999) at the neurocognitive level in a healthy volunteer sample. A total of 114 healthy Caucasian volunteers completed genotyping for NRG1 rs3924999 and infrared oculographic assessment of AS and SPEM (at target velocities of 12 degrees , 24 degrees and 36 degrees per second). Additionally, self-report questionnaires of schizotypy, neuroticism, attention deficit hyperactivity and obsessive-compulsive traits were included. A significant effect of rs3924999 genotype, with gender as a covariate, was found for AS amplitude gain (P < 0.01), with an increasing number of A alleles being associated with increasingly hypermetric performance. No statistically significant associations were found for other AS and SPEM variables or questionnaire scores. These findings indicate that NRG1 rs3924999 affects spatial accuracy on the AS task, suggesting an influence of the gene on the neural mechanisms underlying visuospatial sensorimotor transformations, a mechanism that has been previously found to be impaired in patients with schizophrenia and their relatives. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 224 | Neurosci. Lett. 2010 Jun 478: 9-13 |
| PMID | 20435087 |
| Title | Association analysis of Neuregulin 1 candidate regions in schizophrenia and bipolar disorder. |
| Abstract | schizophrenia (SCZ) and bipolar disorder (BPD) are severe heritable psychiatric disorders involving a complex genetic aetiology. Neuregulin 1 (NRG1) is a leading candidate gene for SCZ, and has recently been implicated in BPD. We previously reported association of two NRG1 haplotypes with SCZ and BPD in a Scottish case-control sample. One haplotype is located at the 5' end of the gene (region A), and the other is located at the 3' end (region B). Here, association to haplotypes within regions A and B was assessed in patients with SCZ and BPD in a second Scottish case-control sample and in the two Scottish samples combined. Association to region B was also assessed in patients with SCZ and BPD in a German case-control sample, and in all three samples combined. No evidence was found for association in the new samples when analysed individually; however, in the joint analysis of the two Scottish samples, a region B haplotype comprising two SNPs (rs6988339 and rs3757930) was associated with SCZ and the combined case group (SCZ: p=0.0037, OR=1.3, 95% CI: 1.1-1.6; BPD+SCZ: p=0.0080, OR=1.2, 95% CI: 1.1-1.5), with these associations withstanding multiple testing correction at the single-test level (SCZ: p(st)=0.022; BPD+SCZ: p(st)=0.044). This study supports the involvement of NRG1 variants in the less well studied 3' region in conferring susceptibility to SCZ and BPD in the Scottish population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 225 | J. Neurochem. 2010 Jun 113: 1163-76 |
| PMID | 20218976 |
| Title | Molecular and cellular characterization of Neuregulin-1 type IV isoforms. |
| Abstract | Numerous genetic studies associated the Neuregulin 1 (NRG1) Icelandic haplotype (HAP(ice)), and its single nucleotide polymorphism SNP8NRG243177 [T/T], with schizophrenia. Because SNP8NRG243177 [T/T] has characteristics of a functional polymorphism that maps close to NRG1 type IV coding sequences, our initial goal was to map precisely the human type IV transcription initiation site. We determined that the initiation site is 23 bp upstream of the previously reported type IV exon, and that no other transcripts map to the SNP8NRG243177 region. Because NRG1 type IV transcripts are specific to human, we isolated full-length NRG1 type IV cDNAs from human hippocampi and expressed them in non-neural cells and dissociated rat hippocampal neurons to study protein expression, processing and function. Using an antiserum we generated against the NRG1 type IV-specific N-terminus, we found that the protein is targeted to the cell surface where PKC activation promotes its cleavage and release of the extracellular domain. Conditioned medium derived from type IV expressing cells stimulates ErbB receptor phosphorylation, as well as downstream Akt and Erk signaling, demonstrating that NRG1 type IV possesses biological activity similar to other releasable NRG1 isoforms. To study the subcellular targeting of distinct isoforms, neurons were transfected with the Ig-domain-containing NRG1 types I and IV, or the cysteine-rich domain type III isoform. Three dimensional confocal images from transfected neurons indicate that, whereas all isoforms are expressed on somato-dendritic membranes, only the type III-cysteine-rich domain isoform is detectable in distal axons. These results suggest that NRG1 type IV expression levels associated with SNP8NRG243177 [T/T] can selectively modify signaling of NRG1 released from somato-dendritic compartments, in contrast to the type III NRG1 that is also associated with axons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 226 | World J. Biol. Psychiatry 2010 Mar 11: 243-50 |
| PMID | 20218788 |
| Title | Gene expression of neuregulin-1 isoforms in different brain regions of elderly schizophrenia patients. |
| Abstract | One important risk gene in schizophrenia is neuregulin-1 (NRG1), which is expressed in different isoforms in the brain. To determine if alterations of NRG1 are present in schizophrenia, we measured gene expression of NRG1 and its main isoforms as well as the impact of genetic variation of NRG1 in an exploratory study examining three brain regions instead of only one as published so far. In all, we examined post-mortem samples from 11 schizophrenia patients and eight normal subjects. We investigated gene expression of total NRG1 and isoforms I, II and III by real-time PCR in the prefrontal cortex (Brodmann areas 9 and 10) and right hippocampal tissue. For the genetic study, we genotyped the NRG1 polymorphism SNP8NRG221533, which is within the core haplotype of the original publication. Compared to controls, gene expression of the NRG1 isoform I was decreased and isoform II increased in the prefrontal cortex (BA10) of schizophrenia patients. There were no statistically significant differences between individuals carrying at least one C allele of SNP8NRG221533 compared to individuals homozygous for the T allele. The decreased expression of NRG1 isoform I and overexpression of isoform II may be related to deficits in receptor function as well as abnormal migration and myelination. However, our study sample was small and results of this exploratory study should be verified in a larger sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 227 | J. Alzheimers Dis. 2010 -1 20: 561-7 |
| PMID | 20182055 |
| Title | No association between neuregulin 1 and psychotic symptoms in Alzheimer's disease patients. |
| Abstract | Alzheimer's disease (AD) patients commonly suffer from behavioral and psychological symptoms of dementia (BPSD). Variants within the neuregulin-1 (NRG1) gene have been investigated both in early onset psychiatric disorders, such as schizophrenia and recently in AD patients with psychosis. In this study, we analyzed NRG1 variants in AD patients with and without psychosis. Our large cohort of 399 probable AD patients had longitudinal information on the BPSD, which was used to dichotomize patients into whether they had ever suffered from psychotic symptoms within the study period. The NRG1 single nucleotide polymorphisms rs3924999, rs35753505 (SNP8NRG221533) and the microsatellites 478B14-848 and 420M9-1395 were investigated for association with psychosis using genotype, allele, and haplotype analyses. No associations were found between any of these variants or haplotypic combinations with delusions, hallucinations, psychosis, or elation/mania in our cohort. Positive associations with polymorphisms and haplotype combinations of NRG1 have been reported in psychiatric disorders. One previous study found an association with psychosis in AD, with a SNP outside the haplotype block first reported for association with schizophrenia. We found no association with any of these variants in our cohort. Further investigations of this region on chromosome 8 are clearly required, with replication in different large longitudinal cohorts. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 228 | Eur. J. Neurosci. 2010 Jan 31: 349-58 |
| PMID | 20074216 |
| Title | Schizophrenia-related endophenotypes in heterozygous neuregulin-1 'knockout' mice. |
| Abstract | Neuregulin-1 (NRG1) has been shown to play a role in glutamatergic neurotransmission and is a risk gene for schizophrenia, in which there is evidence for hypoglutamatergic function. Sensitivity to the behavioural effects of the psychotomimetic N-methyl-D-aspartate receptor antagonists MK-801 and phencyclidine (PCP) was examined in mutant mice with heterozygous deletion of NRG1. Social behaviour (sociability, social novelty preference and dyadic interaction), together with exploratory activity, was assessed following acute or subchronic administration of MK-801 (0.1 and 0.2 mg/kg) or PCP (5 mg/kg). In untreated NRG1 mutants, levels of glutamate, N-acetylaspartate and GABA were determined using high-performance liquid chromatography and regional brain volumes were assessed using magnetic resonance imaging at 7T. NRG1 mutants, particularly males, displayed decreased responsivity to the locomotor-activating effects of acute PCP. Subchronic MK-801 and PCP disrupted sociability and social novelty preference in mutants and wildtypes and reversed the increase in both exploratory activity and social dominance-related behaviours observed in vehicle-treated mutants. No phenotypic differences were demonstrated in N-acetylaspartate, glutamate or GABA levels. The total ventricular and olfactory bulb volume was decreased in mutants. These data indicate a subtle role for NRG1 in modulating several schizophrenia-relevant processes including the effects of psychotomimetic N-methyl-D-aspartate receptor antagonists. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 229 | Neuroimage 2010 Nov 53: 985-91 |
| PMID | 20036336 |
| Title | The effect of Neuregulin 1 on neural correlates of episodic memory encoding and retrieval. |
| Abstract | Neuregulin 1 (NRG1) has been found to be associated with schizophrenia. Impaired performance in episodic memory tasks is an often replicated finding in this disorder. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal and medial temporal areas. Therefore, it is of interest whether genes associated with the disorder, such as NRG1, modulate episodic memory performance and its neural correlates. Ninety-four healthy individuals performed an episodic memory encoding and a retrieval task while brain activation was measured with functional MRI. All subjects were genotyped for the single nucleotide polymorphism (SNP) rs35753505 in the NRG1 gene. The effect of genotype on brain activation was assessed with fMRI during the two tasks. While there were no differences in performance, brain activation in the cingulate gyrus (BA 24), the left middle frontal gyrus (BA 9), the bilateral fusiform gyrus and the left middle occipital gyrus (BA 19) was positively correlated with the number of risk alleles in NRG1 during encoding. During retrieval brain activation was positively correlated with the number of risk alleles in the left middle occipital gyrus (BA 19). NRG1 genotype does modulate brain activation during episodic memory processing in key areas for memory encoding and retrieval. The results suggest that subjects with risk alleles show hyperactivations in areas associated with elaborate encoding strategies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 230 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Apr 153B: 792-801 |
| PMID | 19937977 |
| Title | Association study of NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A with schizophrenia and symptom severity in a Hungarian sample. |
| Abstract | Genetic association studies have yielded extensive but frequently inconclusive data about genetic risk factors for schizophrenia. Clinical and genetic heterogeneity are possible factors explaining the inconsistent findings. The objective of this study was to test the association of commonly incriminated candidate genes with two clinically divergent subgroups, non-deficit (SZ-ND) and deficit-schizophrenia (SZ-D), and symptom severity, in order to test for replication of previously reported results. A homogeneous sample of 280 schizophrenia patients and 230 healthy controls of Hungarian, Caucasian descent were genotyped for polymorphisms in schizophrenia candidate genes NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A. Patients were divided into the diagnostic subgroups of SZ-ND and SZ-D using the Schedule for Deficit Syndrome (SDS), and assessed clinically by the Positive and Negative Symptom Scale (PANSS). SNP8NRG241930 in NRG1 and rs1011313 in DTNBP1 were associated with SZ-ND (P = 0.04 and 0.03, respectively). Polymorphisms in RGS4, G72/G30, and PIP5K2A were neither associated with SZ-ND nor with SZ-D. SNP8NRG241930 showed association with the PANSS cognitive and hostility/excitability factors, rs1011313 with the negative factor and SDS total score, and rs10917670 in RGS4 was associated with the depression factor. Although these results replicate earlier findings about the genetic background of SZ-ND and SZ-D only partially, our data seem to confirm previously reported association of NRG1 with schizophrenia without prominent negative symptoms. It was possible to detect associations of small-to-medium effect size between the investigated candidate genes and symptom severity. Such studies have the potential to unravel the possible connection between genetic and clinical heterogeneity in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 231 | Neuroimage 2010 Nov 53: 1016-22 |
| PMID | 19913623 |
| Title | Additive effect of NRG1 and DISC1 genes on lateral ventricle enlargement in first episode schizophrenia. |
| Abstract | Neuregulin 1 (NRG1) and Disrupted-in-schizophrenia (DISC1) genes, which are candidate genes for schizophrenia, are implicated in brain development. We have previously reported an association between the T allele of the rs6994992 SNP within NRG1 gene and lateral ventricle (LV) enlargement in first-episode schizophrenia patients. Moreover, transgenic mice with mutant DISC1 have also been reported as showing LV enlargement. In this study, we examined the possible interactive effects of NRG1 and DISC1 on brain volumes in a sample of first-episode schizophrenia patients. Ninety-one patients experiencing their first episode of schizophrenia underwent genotyping of three SNPs within DISC1 and structural brain MRI. These results were combined with our previously reported genotypes on three SNPs within NRG1. The T/T genotype of rs2793092 SNP in DISC1 was significantly associated with increased LV volume. However, taking into account the rs6994992 SNP in the NRG1 gene, which was also associated with LV volume in a previous study, the DISC1 SNP only predicted LV enlargement among those patients carrying the T allele in the NRG1 SNP. Those patients with the "at risk" allelic combinations in both genes had LV volumes which were 48% greater than those with none of the allelic combinations. Our findings suggest that NRG1 and DISC1 genes may be associated with brain abnormalities in schizophrenia through their influence on related pathways of brain development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 232 | Eur Arch Psychiatry Clin Neurosci 2010 Mar 260: 101-11 |
| PMID | 19856012 |
| Title | Gene expression of NMDA receptor subunits in the cerebellum of elderly patients with schizophrenia. |
| Abstract | To determine if NMDA receptor alterations are present in the cerebellum in schizophrenia, we measured NMDA receptor binding and gene expression of the NMDA receptor subunits in a post-mortem study of elderly patients with schizophrenia and non-affected subjects. Furthermore, we assessed influence of genetic variation in the candidate gene neuregulin-1 (NRG1) on the expression of the NMDA receptor in an exploratory study. Post-mortem samples from the cerebellar cortex of ten schizophrenic patients were compared with nine normal subjects. We investigated NMDA receptor binding by receptor autoradiography and gene expression of the NMDA receptor subunits NR1, NR2A, NR2B, NR2C and NR2D by in situ hybridization. For the genetic study, we genotyped the NRG1 polymorphism rs35753505 (SNP8NRG221533). Additionally, we treated rats with the antipsychotics haloperidol or clozapine and assessed cerebellar NMDA receptor binding and gene expression of subunits to examine the effects of antipsychotic treatment. Gene expression of the NR2D subunit was increased in the right cerebellum of schizophrenic patients compared to controls. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of the NR2C subunit in the right cerebellum, compared to individuals homozygous for the T allele. Correlation with medication parameters and the animal model revealed no treatment effects. In conclusion, increased NR2D expression results in a hyperexcitable NMDA receptor suggesting an adaptive effect due to receptor hypofunction. The decreased NR2C expression in NRG1 risk variant may cause a deficit in NMDA receptor function. This supports the hypothesis of an abnormal glutamatergic neurotransmission in the right cerebellum in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 233 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Jan 153B: 103-13 |
| PMID | 19367581 |
| Title | Identification of neuroglycan C and interacting partners as potential susceptibility genes for schizophrenia in a Southern Chinese population. |
| Abstract | Chromosome 3p was reported by previous studies as one of the regions showing strong evidence of linkage with schizophrenia. We performed a fine-mapping association study of a 6-Mb high-LD and gene-rich region on 3p in a Southern Chinese sample of 489 schizophrenia patients and 519 controls to search for susceptibility genes. In the initial screen, 4 SNPs out of the 144 tag SNPs genotyped were nominally significant (P < 0.05). One of the most significant SNPs (rs3732530, P = 0.0048) was a non-synonymous SNP in the neuroglycan C (NGC, also known as CSPG5) gene, which belongs to the neuregulin family. The gene prioritization program Endeavor ranked NGC 8th out of the 129 genes in the 6-Mb region and the highest among the genes within the same LD block. Further genotyping of NGC revealed 3 more SNPs to be nominally associated with schizophrenia. Three other genes (NRG1, ErbB3, ErbB4) involved in the neuregulin pathways were subsequently genotyped. Interaction analysis by multifactor dimensionality reduction (MDR) revealed a significant two-SNP interaction between NGC and NRG1 (P = 0.015) and three-SNP interactions between NRG1 and ErbB4 (P = 0.009). The gene NGC is exclusively expressed in the brain. It is implicated in neurodevelopment in rats and was previously shown to promote neurite outgrowth. Methamphetamine, a drug that may induce psychotic symptoms, was reported to alter the expression of NGC. Taken together, these results suggest that NGC may be a novel candidate gene, and neuregulin signaling pathways may play an important role in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 234 | Arch. Gen. Psychiatry 2010 Oct 67: 991-1001 |
| PMID | 20921115 |
| Title | Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls. |
| Abstract | NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. schizophrenia is a complex disorder, with etiology likely due to epistasis. To examine epistasis between NRG1 and selected N-methyl-d-aspartate-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, and NOS1AP. schizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls. A referred sample of schizophrenic patients (n = 296) meeting DSM-IV criteria for schizophrenia spectrum disorder and a volunteer sample of controls for case-control comparison (n = 365) and a separate volunteer sample of controls for neuroimaging (n = 172). Epistatic association between single-nucleotide polymorphisms (SNPs) and case-control status; epistatic association between SNPs and the blood oxygen level-dependent physiological response during working memory measured by functional magnetic resonance imaging. We observed interaction between NRG1 5' and 3' SNPs rs4560751 and rs3802160 (likelihood ratio test P = .00020) and schizophrenia, which was validated using functional magnetic resonance imaging of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in the dorsolateral prefrontal cortex (P = .015, familywise error corrected). We observed epistasis between NRG1 (rs10503929; Thr286/289/294Met) and its receptor ERBB4 (rs1026882; likelihood ratio test P = .035); a 3-way interaction with these 2 SNPs and AKT1 (rs2494734) was also observed (odds ratio, 27.13; 95% confidence interval, 3.30-223.03; likelihood ratio test P = .042). These same 2- and 3-way interactions were further biologically validated via functional magnetic resonance imaging: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these 2 together with AKT1, were disproportionately less efficient in dorsolateral prefrontal cortex processing. Lower-level interactions were not observed between NRG1 /ERBB4 and AKT1 in association or neuroimaging, consistent with biological evidence that NRG1 × ERBB4 interaction modulates downstream AKT1 signaling. Our data suggest complex epistatic effects implicating an NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 235 | Schizophr. Res. 2010 Dec 124: 200-7 |
| PMID | 20926259 |
| Title | Decreased Neuregulin 1 C-terminal fragment in Brodmann's area 6 of patients with schizophrenia. |
| Abstract | Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. A decrease in NRG1-ErbB4 signalling has also been associated with the disease. ?-amyloid precursor protein-cleaving enzyme (BACE1) processes type III NRG1 precursor, a major neuregulin variant expressed in the brain, to release NRG1 fragments that trigger signalling events and activation of neurotransmitter receptors. Experimental evidence suggests that muscarinic acetylcholine receptors (CHRM) regulate BACE1 expression. Having recently shown that CHRM1 levels are decreased selectively in frontal cortex regions of a subpopulation of schizophrenic patients (muscarinic receptor deficit schizophrenia, MRDS) we aimed to compare the protein expression of BACE1 and NRG1 in the agranular frontal cortex Brodmann's area 6 of SCZ subjects with normal levels of CHRM1 (N = 19), MRDS (N = 20), and age/gender-matched non-psychiatric (healthy) controls (HC; N = 20). Western blot analysis of post-mortem samples showed that the levels of BACE1 and full-length NRG1 precursor (130 kDa) did not differ significantly between the three groups. In contrast, the levels of the NRG1 C-terminal fragment (NRG1-CTF) were decreased by approximately 50% in both schizophrenic groups compared to the HC group (p<0.0027). The ratio of NRG1-CTF versus NRG1 precursor was significantly reduced in the SCZ groups compared to the HC group (p = 0.051). There was no correlation between the levels of either full-length NRG1, NRG1-CTF, or BACE1 and the final recorded doses of antipsychotic drugs for the subjects with schizophrenia. A positive correlation was found between BACE1 and full-length NRG1 precursor in the HC group (r(2) = 0.671, p<0.001) but not in the schizophrenic groups. These data suggest that the proteolytic processing of NRG1 is impaired in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 236 | Genes Brain Behav. 2010 Aug 9: 621-7 |
| PMID | 20497232 |
| Title | Association of Neuregulin 1 rs3924999 genotype with antisaccades and smooth pursuit eye movements. |
| Abstract | Neuregulin 1 (NRG1) has been identified as one of the leading candidate genes for schizophrenia. However, its functional mechanisms and its effects on neurocognition remain unclear. In this study, we used two well-established oculomotor endophenotypes, the antisaccade (AS) and smooth pursuit eye movement (SPEM) tasks, to investigate the functional mechanisms of a single nucleotide polymorphism (SNP) in NRG1 (rs3924999) at the neurocognitive level in a healthy volunteer sample. A total of 114 healthy Caucasian volunteers completed genotyping for NRG1 rs3924999 and infrared oculographic assessment of AS and SPEM (at target velocities of 12 degrees , 24 degrees and 36 degrees per second). Additionally, self-report questionnaires of schizotypy, neuroticism, attention deficit hyperactivity and obsessive-compulsive traits were included. A significant effect of rs3924999 genotype, with gender as a covariate, was found for AS amplitude gain (P < 0.01), with an increasing number of A alleles being associated with increasingly hypermetric performance. No statistically significant associations were found for other AS and SPEM variables or questionnaire scores. These findings indicate that NRG1 rs3924999 affects spatial accuracy on the AS task, suggesting an influence of the gene on the neural mechanisms underlying visuospatial sensorimotor transformations, a mechanism that has been previously found to be impaired in patients with schizophrenia and their relatives. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 237 | Eur Arch Psychiatry Clin Neurosci 2010 Mar 260: 101-11 |
| PMID | 19856012 |
| Title | Gene expression of NMDA receptor subunits in the cerebellum of elderly patients with schizophrenia. |
| Abstract | To determine if NMDA receptor alterations are present in the cerebellum in schizophrenia, we measured NMDA receptor binding and gene expression of the NMDA receptor subunits in a post-mortem study of elderly patients with schizophrenia and non-affected subjects. Furthermore, we assessed influence of genetic variation in the candidate gene neuregulin-1 (NRG1) on the expression of the NMDA receptor in an exploratory study. Post-mortem samples from the cerebellar cortex of ten schizophrenic patients were compared with nine normal subjects. We investigated NMDA receptor binding by receptor autoradiography and gene expression of the NMDA receptor subunits NR1, NR2A, NR2B, NR2C and NR2D by in situ hybridization. For the genetic study, we genotyped the NRG1 polymorphism rs35753505 (SNP8NRG221533). Additionally, we treated rats with the antipsychotics haloperidol or clozapine and assessed cerebellar NMDA receptor binding and gene expression of subunits to examine the effects of antipsychotic treatment. Gene expression of the NR2D subunit was increased in the right cerebellum of schizophrenic patients compared to controls. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of the NR2C subunit in the right cerebellum, compared to individuals homozygous for the T allele. Correlation with medication parameters and the animal model revealed no treatment effects. In conclusion, increased NR2D expression results in a hyperexcitable NMDA receptor suggesting an adaptive effect due to receptor hypofunction. The decreased NR2C expression in NRG1 risk variant may cause a deficit in NMDA receptor function. This supports the hypothesis of an abnormal glutamatergic neurotransmission in the right cerebellum in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 238 | J. Neurosci. 2011 Aug 31: 11628-32 |
| PMID | 21832192 |
| Title | Genetic association of ErbB4 and human cortical GABA levels in vivo. |
| Abstract | NRG1-ErbB4 signaling controls inhibitory circuit development in the mammalian cortex through ErbB4-dependent regulation of GABAergic interneuron connectivity. Common genetic variation in ErbB4 (rs7598440) has been associated with ErbB4 messenger RNA levels in the human cortex and risk for schizophrenia. Recent work demonstrates that Erbb4 is expressed exclusively on inhibitory interneurons, where its presence on parvalbumin-positive cells mediates the effects of NRG1 on inhibitory circuit formation in the cortex. We therefore hypothesized that genetic variation in ErbB4 at rs7598440 would impact indices of GABA concentration in the human cortex. We tested this hypothesis in 116 healthy volunteers by measuring GABA and GLX (glutamate + glutamine) with proton magnetic resonance spectroscopy in the dorsal anterior cingulate gyrus. ErbB4 rs7598440 genotype significantly predicted cortical GABA concentration (p = 0.014), but not GLX (p = 0.51), with A allele carriers having higher GABA as predicted by the allelic impact on ErbB4 expression. These data establish an association of ErbB4 and GABA in human brain and have implications for understanding the pathogenesis of schizophrenia and other psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 239 | Psychol Med 2011 Feb 41: 263-76 |
| PMID | 20102668 |
| Title | Do COMT, BDNF and NRG1 polymorphisms influence P50 sensory gating in psychosis? |
| Abstract | Auditory P50 sensory gating deficits correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The well-supported role of catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin 1 (NRG1) genes in neurodevelopment and cognition make a strong theoretical case for their influence on the P50 endophenotype. The possible role of NRG1, COMT Val158Met and BDNF Val66Met gene polymorphisms on the P50 endophenotype was examined in a large sample consisting of psychotic patients, their unaffected relatives and unrelated healthy controls using linear regression analyses. Although P50 deficits were present in patients and their unaffected relatives, there was no evidence for an association between NRG1, COMT Val158Met or BDNF Val66Met genotypes and the P50 endophenotype. The evidence from our large study suggests that any such association between P50 indices and NRG1, COMT Val158Met or BDNF Val66Met genotypes, if present, must be very subtle. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 240 | Nat. Med. 2011 Apr 17: 470-8 |
| PMID | 21441918 |
| Title | Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors. |
| Abstract | Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1?-ErbB4 (NRG1?-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1?-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1?-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1?-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 241 | Curr. Opin. Genet. Dev. 2011 Jun 21: 262-70 |
| PMID | 21295966 |
| Title | Neuregulin signaling, cortical circuitry development and schizophrenia. |
| Abstract | Neuregulin-1 (NRG1) and its receptor ErbB4 are encoded by genes that have been repeatedly linked to schizophrenia. Both genes are thought to play important roles in the development of brain circuitry, but their precise contribution to the disease process remains unknown. In this review, we summarize novel findings on the biological function of NRG1 and ErbB4 in mice, with a focus on the development of inhibitory circuits in the cerebral cortex. We will also discuss how this basic knowledge may help us to understand the etiology of schizophrenia, and eventually lead to the development of novel therapies for treating the disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 242 | Psychiatry Res 2011 Feb 191: 133-7 |
| PMID | 21232925 |
| Title | Genetic variants in the ErbB4 gene are associated with white matter integrity. |
| Abstract | Variations in the signalling NRG1-ErbB4 pathway have been associated with genetic susceptibility for both bipolar disorder and schizophrenia, although the underlying neural mechanisms are still uncertain. Reduced integrity of the anterior limb of the internal capsule (ALIC) has been found in association with risk-associated genetic variation in the 5' region of the NRG1 gene. We hypothesised that variation in the gene encoding the NRG1 receptor, ErbB4, would also be associated with reduced ALIC integrity and with cognitive impairments characteristic of individuals with bipolar disorder and schizophrenia. Using diffusion tensor imaging (DTI), we examined the white matter integrity associations of the ErbB4 polymorphism rs4673628, which resides within intron 12 of the gene encoding ErbB4, in 36 healthy individuals. We also sought to clarify the cognitive effects of any findings. We found that genetic variation at the rs4673628 locus in the ErbB4 gene was significantly associated with ALIC white matter integrity which was also significantly and positively associated with mnemonic function. These findings provide further evidence to support a key role of NRG1-ErbB4 signalling in the pathophysiology of major mental disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 243 | Zh Nevrol Psikhiatr Im S S Korsakova 2011 -1 111: 53-7 |
| PMID | 21716252 |
| Title | [The association between the NRG1 gene polymorphism and cognitive functions in patients with schizophrenia and healthy controls]. |
| Abstract | NRG1 is a strong candidate for schizophrenia though its role in the pathogenesis of the disease remains unknown. One of the approaches to study mechanisms underlying the association between NRG1 and schizophrenia is to investigate the association between a gene and an endophenotype of schizophrenia, e.g., cognitive dysfunctions. Authors looked for the association of 478B14-848 ? 420M9-1395 microsatellites with semantic verbal fluency, working and episodic memory in 338 patents with schizophrenia, 162 their unaffected relatives and 316 healthy controls from the Russian population. It was found associations between allele 0 at 478B14-848 (220 bp) and long-term episodic memory and between allele 0 at 420M9-1395 (274 bp) and short-term memory in schizophrenic patients. The frequency of homozygotes for 420M9-1395 was higher in the group of patients as compared to controls. In conclusion, the risk allele 0 at 420M9-1395 is associated with the short-term memory deficit while allele 0 at 478B14-848 is protective for long-term memory deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 244 | Psychiatr. Genet. 2011 Feb 21: 47-9 |
| PMID | 20978455 |
| Title | No NRG1 V266L in Chinese patients with schizophrenia. |
| Abstract | NRG1 is one of the best-supported schizophrenia (SZ) susceptibility genes. A NRG1 V266L missense mutation has been found to be associated with SZ in several populations. V266L is not in linkage disequilibrium with any of the SZ-associated NRG1 haplotypes described thus far, and may represent an independent SZ susceptibility locus within NRG1 gene. V266 is a highly conserved residue and its substitution is predicted to have a deleterious effect on the protein. As there are no data for V266L in Chinese, and given the potential relevance of this mutation, we investigated the V266L prevalence in 270 Chinese patients with schizophrenia and 270 ethnically matched controls. V266L was found neither in patients nor in controls. Lack of replication of an association across populations may be because of the differences in linkage disequilibrium structure or allele frequencies. Some true associations may not be replicated regardless of the sample size of the study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 245 | Neuropsychopharmacol Hung 2011 Dec 13: 205-10 |
| PMID | 22184188 |
| Title | Genetic predisposition to schizophrenia: what did we learn and what does the future hold? |
| Abstract | schizophrenia is a complex, devastating brain disorder with clear genetic and environmental contributions to the emergence of the disease. In the last several decades of research hundreds of millions of dollars were spent of the elusive search for schizophrenia susceptibility genes, but the results have been meager. Researchers have identified a number of genetic variants that predispose the brain to developing the disease, yet alone they can explain only a very small number of the schizophrenia occurrence. Vulnerability in DISC1, NRG1, DTNBP1, RGS4, KCNH2, COMT, AKT1 and other putative schizophrenia genes, together with copy number variants, leave unexplained the vast majority of diseased cases. Furthermore, most of the uncovered disease-associated genetic variants have been inconsistently replicated across multiple cohorts and do not lead to altered protein structure. In summary, we argue that large-scale genetic studies will not provide us with the answers we seek: we have to accept that there are no schizophrenia-predisposing genes with large effect sizes, and due to the diversity of findings, genetics-based novel therapies of schizophrenia are not realistic. The new treatments will have to come from functional studies of intracellular pathways and understanding the confluence of environmental influences and genetic predisposition, and their combined effects on developmental mechanisms and intracellular cascades. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 246 | PLoS ONE 2011 -1 6: e27337 |
| PMID | 22087295 |
| Title | Expression of the neuregulin receptor ErbB4 in the brain of the rhesus monkey (Macaca mulatta). |
| Abstract | We demonstrated recently that frontal cortical expression of the Neuregulin (NRG) receptor ErbB4 is restricted to interneurons in rodents, macaques, and humans. However, little is known about protein expression patterns in other areas of the brain. In situ hybridization studies have shown high ErbB4 mRNA levels in various subcortical areas, suggesting that ErbB4 is also expressed in cell types other than cortical interneurons. Here, using highly-specific monoclonal antibodies, we provide the first extensive report of ErbB4 protein expression throughout the cerebrum of primates. We show that ErbB4 immunoreactivity is high in association cortices, intermediate in sensory cortices, and relatively low in motor cortices. The overall immunoreactivity in the hippocampal formation is intermediate, but is high in a subset of interneurons. We detected the highest overall immunoreactivity in distinct locations of the ventral hypothalamus, medial habenula, intercalated nuclei of the amygdala and structures of the ventral forebrain, such as the islands of Calleja, olfactory tubercle and ventral pallidum, and medium expression in the reticular thalamic nucleus. While this pattern is generally consistent with ErbB4 mRNA expression data, further investigations are needed to identify the exact cellular and subcellular sources of mRNA and protein expression in these areas. In contrast to in situ hybridization in rodents, we detected only low levels of ErbB4-immunoreactivity in mesencephalic dopaminergic nuclei but a diffuse pattern of immunofluorescence that was medium in the dorsal striatum and high in the ventral forebrain, suggesting that most ErbB4 protein in dopaminergic neurons could be transported to axons. We conclude that the NRG-ErbB4 signaling pathway can potentially influence many functional systems throughout the brain of primates, and suggest that major sites of action are areas of the "corticolimbic" network. This interpretation is functionally consistent with the genetic association of NRG1 and ERBB4 with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 247 | Prog. Neurobiol. 2011 Nov 95: 275-300 |
| PMID | 21907759 |
| Title | Schizophrenia: susceptibility genes, dendritic-spine pathology and gray matter loss. |
| Abstract | Gray matter loss in the cortex is extensive in schizophrenia, especially in the prefrontal-temporal-network (PTN). Several molecules such as neuregulin-1 (NRG1) and its ErbB4 receptor are encoded by candidate susceptibility genes for schizophrenia. The question arises as to how these genes might contribute to the observed changes in gray matter. It is suggested that one pathway involves molecules such as NRG1/ErbB4 determining the efficacy of N-methyl-D-aspartate receptors (NMDARs) found on dendritic spines at synapses in the PTN. The growth of dendritic spines is modulated by NRG1/ErbB4 through NMDARs as these activate small Rho-GTPases, such as kalirin, which control the actin cytoskeleton in the spines responsible for their growth. Another pathway involves NRG1/ErbB determining the proliferation and differentiation of oligodendrocytes in the white matter as well as their capacity for myelination, the integrity of which determines the stability of nerve terminals on dendritic spines. A causal chain is established between failure of the products of susceptibility genes for schizophrenia, the decrease of dendritic spines and synaptic terminals, and the loss of gray matter. It is suggested than an important focus for future research in schizophrenia is to identify interventions that prevent the loss of dendritic spines and synapses during the prodromal period or earlier during development as well as to re-establish dendritic spines and synapses lost subsequent to this period. This will help reestablish neural networks in the PTN and so the loss of gray matter in the PTN. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 248 | Neuropharmacology 2011 Dec 61: 1413-8 |
| PMID | 21903113 |
| Title | Biodistribution and brain permeability of the extracellular domain of neuregulin-1-?1. |
| Abstract | Neuregulin-1 (NRG1) belongs to a large family of growth and differentiation factors with a key role in the development and maintenance of the brain. Genetic association of NRG1 within brain disorders such as Alzheimer's disease, schizophrenia and neuroprotective properties of certain NRG1 isoforms have led to a variety of studies in corresponding disease models. In the present work, we investigated NRG1 with regard to its peripheral and central biodistribution after systemic application. We first-time radiolabeled the entire biologically active extracellular domain of NRG1 isotype-?1 (NRG1-?1 ECD; aa 2-246) with iodine-125 and administered it peripherally to healthy adult C57Bl6 mice. Blood kinetics and relative organ distribution of (125)I-labeled NRG1-?1 ECD were determined. The blood level of NRG1-?1 ECD peaked within the first hour after intraperitoneal (i.p.) application. The brain-blood ratios of (125)I-labeled NRG1-?1 ECD were time-dependently 150-370% higher compared to the brain impermeable control, (131)I-labeled bovine serum albumin. Autoradiographs of brain slices demonstrated that (125)I-labeled NRG1-?1 ECD accumulated in several regions of the brain e.g. frontal cortex, striatum and ventral midbrain containing the substantia nigra. In addition we found histochemical and biochemical evidence that phosphorylation of the NRG1 prototype receptor ErbB4 was increased in these regions after systemic application of NRG1-?1 ECD. Our data suggest that NRG1-?1 ECD passes the blood-brain barrier and activates cerebral ErbB4 receptors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 249 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2011 Dec 28: 620-4 |
| PMID | 22161091 |
| Title | [Expressional changes of neuregulin-1 gene mRNA in peripheral blood from schizophrenia patients]. |
| Abstract | To explore the effect of anti-psychotic treatment on the expression of Neuregulin-1 (NRG1) mRNA in the peripheral blood lymphocytes of schizophrenia patients. The NRG1 mRNA in peripheral blood lymphocytes was measured using semi-quantitative reverse transcription (RT)-PCR in 80 first-onset schizophrenia patients, 37 sibling controls and 83 non-related controls. The patients were treated with risperdone and quetiapine for 4 weeks. Positive and negative symptom scale (PANSS) was used to evaluate the severity and clinical efficacy. Prior to the treatment, the expression of NRG1 mRNA expression was significantly lower in patients than other two groups (F=73.004, P=0.000). From the second week on, the level of NRG1 mRNA expression in patients became significantly higher than before and gradually increased, whilst no significant difference between sib and non-sib controls. Prior to the treatment, there was significant correlation (r=-0.232, P=0.038) between the level of NRG1 mRNA and PANSS scores. Four weeks after the treatment, a significant correlation between the reduction rate of PANSS and the change of NRG1 mRNA (r=0.27, P=0.016). The expression of NRG1 gene mRNA is associated with schizophrenia. Decreased expression of NRG1 may play a role in the development of schizophrenia, which can be improved by anti-psychotic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 250 | Schizophr. Res. 2011 Sep 131: 52-7 |
| PMID | 21745728 |
| Title | Lack of association to a NRG1 missense polymorphism in schizophrenia or bipolar disorder in a Costa Rican population. |
| Abstract | A missense polymorphism in the NRG1 gene, Val>Leu in exon 11, was reported to increase the risk of schizophrenia in selected families from the Central Valley region of Costa Rica (CVCR). The present study investigated the relationship between three NRG1 genetic variants, rs6994992, rs3924999, and Val>Leu missense polymorphism in exon 11, in cases and selected controls from an isolated population from the CVCR. Isolated populations can have less genetic heterogeneity and increase power to detect risk variants in candidate genes. Subjects with bipolar disorder (BD, n=358), schizophrenia (SZ, n=273), or unrelated controls (CO, n=479) were genotyped for three NRG1 variants. The NRG1 promoter polymorphism (rs6994992) was related to altered expression of NRG1 Type IV in other studies. The expression of NRG1 type IV in the dorsolateral prefrontal cortex (DLPFC) and the effect of the rs6994992 genotype on expression were explored in a postmortem cohort of BD, SZ, major depressive disorder (MDD) cases, and controls. The missense polymorphism Val>Leu in exon 11 was not significantly associated with schizophrenia as previously reported in a family sample from this population, the minor allele frequency is 4%, thus our sample size is not large enough to detect an association. We observed however an association of rs6994992 with NRG1 type IV expression in DLPFC and a significantly decreased expression in MDD compared to controls. The present results while negative do not rule out a genetic association of these SNPs with BD and SZ in CVCR, perhaps due to small risk effects that we were unable to detect and potential intergenic epistasis. The previous genetic relationship between expression of a putative brain-specific isoform of NRG1 type IV and SNP variation was replicated in postmortem samples in our preliminary study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 251 | Mol. Psychiatry 2011 Jan 16: 37-58 |
| PMID | 19935739 |
| Title | Identification of blood biomarkers for psychosis using convergent functional genomics. |
| Abstract | There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as NRG1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 252 | J Neural Transm (Vienna) 2011 Nov 118: 1621-39 |
| PMID | 21688113 |
| Title | Neurocognitive-genetic and neuroimaging-genetic research paradigms in schizophrenia and bipolar disorder. |
| Abstract | Studies examining intermediate phenotypes such as neurocognitive and neuroanatomical measures along with susceptibility genes are important for improving our understanding of the neural basis of schizophrenia (SZ) and bipolar disorder (BD). In this paper, we review extant studies involving neurocognitive-genetic and neuroimaging-genetic perspectives and particularly related to catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin-1 (NRG1) genes in SZ and BD. In terms of neurocognitive-genetic investigations, COMT and BDNF are the two most studied candidate genes especially in patients with SZ. Whereas BDNF Met carriers perform worse on verbal working memory, problem solving and visuo-spatial abilities, COMT Met carriers perform better in working memory, attention, executive functioning with evidence of genotype by diagnosis interactions including high-risk individuals. In terms of genetic-structural MRI studies, patients with SZ are found to have reductions in the frontal, temporal, parietal cortices, and limbic regions, which are associated with BDNF, COMT, and NRGI genes. Genetic-functional MRI studies in psychotic disorders are sparse, especially with regard to BD. These neurocognitive and neuroimaging findings are associated with genes which are implicated in functional pathways related to neuronal signaling, inter-neuronal communication and neuroplasticity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 253 | Curr Alzheimer Res 2011 May -1: -1 |
| PMID | 21605034 |
| Title | BACE1 Dependent Neuregulin Proteolysis. |
| Abstract | Neuregulin-1 (NRG1), which is also called acetylcholine receptor inducing activity (ARIA) or glial growth factor (GGF), signals as a ligand of ErbB receptors in a variety of important developmental processes but also later in life. NRG1 mediated signaling is crucial for cardiogenesis and the development of the breast. In the nervous system, NRG1 functions are essential for peripheral myelination, the establishment and maintenance of neuromuscular and sensorimotoric systems as well as for the plasticity of cortical neuronal circuits. There is strong evidence that deregulation of NRG1 is involved in breast cancer and schizophrenia. Many splice variants of NRG1 are expressed in the brain and all contain an EGF-like domain, which exerts the NRG1 function by limited proteolysis from its membrane bound precursor protein. In addition, most NRG1 isoforms contain a transmembrane domain, which is processed by ?-secretase after shedding. ?-Secretase (?-site amyloid precursor protein cleaving enzyme 1; BACE1) has been identified based on its role as the rate limiting enzyme of amyloid-?-peptide (A?) production. A? is the major component of amyloid plaques in Alzheimer`s disease (AD). More recently it was shown that Neuregulin-1 activity is highly dependent on the cleavage by BACE1 during early postnatal development. In BACE1 KO mice a role for BACE1 dependent proteolysis of NRG1 in the process of peripheral myelination could be demonstrated. Here we summarize the current knowledge about the role of NRG1 proteolysis for ErbB receptor mediated signaling during development and in Alzheimer`s disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 254 | PLoS ONE 2011 -1 6: e20242 |
| PMID | 21637803 |
| Title | Exonic DNA sequencing of ERBB4 in bipolar disorder. |
| Abstract | The Neuregulin-ErbB4 pathway plays a crucial role in brain development and constitutes one of the most biologically plausible signaling pathways implicated in schizophrenia and, to a lesser extent, in bipolar disorder (BP). However, recent genome-wide association analyses have not provided evidence for common variation in NRG1 or ERBB4 influencing schizophrenia or bipolar disorder susceptibility. In this study, we investigate the role of rare coding variants in ERBB4 in BP cases with mood-incongruent psychotic features, a form of BP with arguably the greatest phenotypic overlap with schizophrenia. We performed Sanger sequencing of all 28 exons in ERBB4, as well as part of the promoter and part of the 3'UTR sequence, hypothesizing that rare deleterious variants would be found in 188 cases with mood-incongruent psychosis from the GAIN BP study. We found 42 variants, of which 16 were novel, although none were non-synonymous or clearly deleterious. One of the novel variants, present in 11.2% of cases, is located next to an alternative stop codon, which is associated with a shortened transcript of ERBB4 that is not translated. We genotyped this variant in the GAIN BP case-control samples and found a marginally significant association with mood-incongruent psychotic BP compared with controls (additive model: OR?=?1.64, P-value?=?0.055; dominant model: OR?=?1.73. P-value?=?0.039). In conclusion, we found no rare variants of clear deleterious effect, but did uncover a modestly associated novel variant that could affect alternative splicing of ERBB4. However, the modest sample size in this study cannot definitively rule out a role for rare variants in bipolar disorder and studies with larger sample sizes are needed to confirm the observed association. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 255 | J. Neurochem. 2011 Jun 117: 1066-74 |
| PMID | 21517849 |
| Title | Systemic administration of neuregulin-1?1 protects dopaminergic neurons in a mouse model of Parkinson's disease. |
| Abstract | Neuregulin-1 (NRG1) is genetically linked to schizophrenia, a disease caused by neurodevelopmental imbalance in dopaminergic function. The NRG1 receptor ErbB4 is abundantly expressed on midbrain dopaminergic neurons. NRG1 has been shown to penetrate blood-brain barrier, and peripherally administered NRG1 activates ErbB4 and leads to a persistent hyperdopaminergic state in neonatal mice. These data prompted us to study the effect of peripheral administration of NRG1 in the context of Parkinson's disease, a neurodegenerative disorder affecting the dopaminergic system in the adult brain. We observed that systemic injections of the extracellular domain of NRG1?(1) (NRG1?(1)-ECD) increased dopamine levels in the substantia nigra and striatum of adult mice. NRG1?(1)-ECD injections also significantly protected the mouse nigrostriatal dopaminergic system morphologically and functionally against 6-hydroxydopamine-induced toxicity in vivo. Moreover, NRG1?(1)-ECD also protected human dopaminergic neurons in vitro against 6-hydroxydopamine. In conclusion, we have identified NRG1?(1)-ECD as a neurotrophic factor for adult mouse and human midbrain dopaminergic neurons with peripheral administratability, warranting further investigation as therapeutic option for Parkinson's disease patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 256 | Zh Nevrol Psikhiatr Im S S Korsakova 2011 -1 111: 53-7 |
| PMID | 21716252 |
| Title | [The association between the NRG1 gene polymorphism and cognitive functions in patients with schizophrenia and healthy controls]. |
| Abstract | NRG1 is a strong candidate for schizophrenia though its role in the pathogenesis of the disease remains unknown. One of the approaches to study mechanisms underlying the association between NRG1 and schizophrenia is to investigate the association between a gene and an endophenotype of schizophrenia, e.g., cognitive dysfunctions. Authors looked for the association of 478B14-848 ? 420M9-1395 microsatellites with semantic verbal fluency, working and episodic memory in 338 patents with schizophrenia, 162 their unaffected relatives and 316 healthy controls from the Russian population. It was found associations between allele 0 at 478B14-848 (220 bp) and long-term episodic memory and between allele 0 at 420M9-1395 (274 bp) and short-term memory in schizophrenic patients. The frequency of homozygotes for 420M9-1395 was higher in the group of patients as compared to controls. In conclusion, the risk allele 0 at 420M9-1395 is associated with the short-term memory deficit while allele 0 at 478B14-848 is protective for long-term memory deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 257 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Jun 35: 924-30 |
| PMID | 21513767 |
| Title | Antipsychotic treatment and neuregulin 1-ErbB4 signalling in schizophrenia. |
| Abstract | Evidence from genetic, transgenic and post-mortem studies has strongly supported the critical role that neuregulin 1 (NRG1) and its ErbB4 receptor plays in the pathophysiology of schizophrenia. This article aims to review current evidence regarding the effects of antipsychotic treatment on NRG1-ErbB4 signalling. NRG1 and ErbB4 knockout mice display abnormal behaviours relevant to certain features of schizophrenia, which could be improved by antipsychotic (clozapine/haloperidol) treatment. In contrast to most NRG1/ErbB4 knockout mice with a decreased NRG1-ErbB4 signalling, the majority post-mortem studies showed an increased NRG1-ErbB4 signalling in schizophrenic patients. These differences could be due to degrees of alteration in risk genes (subtle variations in patients vs pronounced alteration in mutant mice) or the duration of the modification on NRG1 signalling. Various antipsychotics have different effects on NRG1 and ErbB4 expression and signalling that are dependent on treatment duration. Current evidence suggests that a chronic (12weeks) antipsychotic treatment, at least in animal models, could downregulate NRG1-ErbB4 signalling, although an upregulation is seen for a short-term treatment. These effects may be due to multiple binding profiles with various G-coupled protein receptors (e.g. dopamine, and serotonin receptors) of antipsychotics. Studies are needed to investigate the interactions between NRG1-ErbB4 and the other signalling pathways (such as glutamatergic, GABAergic and dopaminergic). Furthermore, the interactions between NRG1/ErbB4 and other schizophrenia suspensibility genes under antipsychotic treatment also require investigation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 258 | Am J Psychiatry 2011 Sep 168: 930-46 |
| PMID | 21498463 |
| Title | Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia. |
| Abstract | The authors used a custom array of 1,536 single-nucleotide polymorphisms (SNPs) to interrogate 94 functionally relevant candidate genes for schizophrenia and identify associations with 12 heritable neurophysiological and neurocognitive endophenotypes in data collected by the Consortium on the Genetics of schizophrenia. Variance-component association analyses of 534 genotyped subjects from 130 families were conducted by using Merlin software. A novel bootstrap total significance test was also developed to overcome the limitations of existing genomic multiple testing methods and robustly demonstrate significant associations in the context of complex family data and possible population stratification effects. Associations with endophenotypes were observed for 46 genes of potential functional significance, with three SNPs at p<10(-4), 27 SNPs at p<10(-3), and 147 SNPs at p<0.01. The bootstrap analyses confirmed that the 47 SNP-endophenotype combinations with the strongest evidence of association significantly exceeded that expected by chance alone, with 93% of these findings expected to be true. Many of the genes interact on a molecular level, and eight genes (e.g., NRG1 and ERBB4) displayed evidence for pleiotropy, revealing associations with four or more endophenotypes. The results collectively support a strong role for genes related to glutamate signaling in mediating schizophrenia susceptibility. This study supports use of relevant endophenotypes and the bootstrap total significance test for identifying genetic variation underlying the etiology of schizophrenia. In addition, the observation of extensive pleiotropy for some genes and singular associations for others suggests alternative, independent pathways mediating pathogenesis in the "group of schizophrenias." |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 259 | J. Neurosci. 2011 Apr 31: 5699-709 |
| PMID | 21490211 |
| Title | Neuregulin-1 signals from the periphery regulate AMPA receptor sensitivity and expression in GABAergic interneurons in developing neocortex. |
| Abstract | Neuregulin-1 (NRG1) signaling is thought to contribute to both neuronal development and schizophrenia neuropathology. Here, we describe the developmental effects of excessive peripheral NRG1 signals on synaptic activity and AMPA receptor expression of GABAergic interneurons in postnatal rodent neocortex. A core peptide common to all NRG1 variants (eNRG1) was subcutaneously administered to mouse pups. Injected eNRG1 penetrated the blood-brain barrier and activated ErbB4 NRG1 receptors in the neocortex, in which ErbB4 mRNA is predominantly expressed by parvalbumin-positive GABAergic interneurons. We prepared neocortical slices from juvenile mice that were receiving eNRG1 subchronically and recorded inhibitory synaptic activity from layer V pyramidal neurons. Postnatal eNRG1 treatment significantly enhanced polysynaptic IPSCs, although monosynaptic IPSCs were not affected. Examination of excitatory inputs to parvalbumin-containing GABAergic interneurons revealed that eNRG1 treatment significantly increased AMPA-triggered inward currents and the amplitudes and frequencies of miniature EPSCs (mEPSCs). Similar effects on mEPSCs were observed in mice treated with a soluble, full-length form of NRG1 type I. Consistent with the electrophysiologic data, expression of the AMPA receptor GluA1 (i.e., GluR1, GluRA) was upregulated in the postsynaptic density/cytoskeletal fraction prepared from eNRG1-treated mouse neocortices. Cortical GABAergic neurons cultured with eNRG1 exhibited a significant increase in surface GluA1 immunoreactivity at putative synaptic sites on their dendrites. These results indicate that NRG1 circulating in the periphery influences postnatal development of synaptic AMPA receptor expression in cortical GABAergic interneurons and may play a role in conditions characterized by GABA-associated neuropathologic processes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 260 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Jun 35: 896-904 |
| PMID | 21371516 |
| Title | Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin1 and their role in schizophrenia. |
| Abstract | schizophrenia is a debilitating neurodevelopmental psychiatric disorder. Both the N-methyl-D-aspartate receptor (NMDAR) and neuregulin1 (NRG1) are key molecules involved in normal brain development that have been linked to schizophrenia pathology and aetiology. The NR2 proteins are critical structural and functional subunits of the NMDAR and are developmentally and spatially regulated. Altered NR2 gene and protein expression has been found in human post-mortem schizophrenia brain tissue together with changes in NRG1 and its receptor ErbB4. The NR2 subunits and ErbB4 share a common anchoring domain on the postsynaptic density and therefore a disruption to either of these molecules may influence the functioning of the other. It has been shown that NRG1 signalling can affect NMDAR levels and function, particularly phosphorylation of the NR2 subunits. However little is known about the possible effects of NMDAR dysfunction on NRG1 signalling, which is important with regards to schizophrenia aetiology as numerous risk factors for the disorder can alter NMDAR functioning during early brain development. This review focuses on the role of the NMDA receptor subunits and NRG1 signalling in schizophrenia and proposes a mechanism by which a disruption to the NMDAR, particularly via altering the balance of NR2 subunits during early development, could influence NRG1 signalling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 261 | Neurosci. Res. 2011 Jun 70: 155-63 |
| PMID | 21352860 |
| Title | The ERBB4 intracellular domain (4ICD) regulates NRG1-induced gene expression in hippocampal neurons. |
| Abstract | The NRG1 growth factor and ERBB4 receptor have been identified as leading schizophrenia risk genes. Although NRG1 and ERBB4 have been shown to modulate neuronal functions involved in schizophrenia, including both GABAergic and glutamatergic synapses, the exact molecular mechanisms remain poorly understood. Here we investigated ERBB4 intracellular domain, 4ICD, transactivator function in rat hippocampal cultures by inhibiting ?-secretase mediated ERBB4 regulated intramembrane proteolysis (RIP). NRG1 stimulation resulted in a dramatic increase in the number of hippocampal cells displaying nuclear 4ICD which was abolished in cultures pretreated with the ?-secretase inhibitor compound E (CE). To identify NRG1-4ICD transactivated genes we compared global gene expression profiles of hippocampal cultures stimulated with NRG1 in the absence or presence of CE. In concordance with the contribution of NRG1-ERBB4 signaling to dendritic spine maturation and schizophrenia, global gene expression analysis followed by Ingenuity Pathway Analysis of the dataset identified NRG1-4ICD regulated genes significantly represented in semaphorin signaling and actin cytoskeletal plasticity and multiple genes with confirmed roles in dendritic spine morphogenesis. Using the power of global gene expression analysis our data provides a proof-of-concept supporting a role for non-canonical NRG1-4ICD signaling in the regulation of gene expression contributing to normal and schizophrenic neuronal function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 262 | J. Neurosci. 2011 Jan 31: 15-25 |
| PMID | 21209185 |
| Title | Neuregulin 1 promotes excitatory synapse development and function in GABAergic interneurons. |
| Abstract | Neuregulin 1 (NRG1) and its receptor ErbB4 are both susceptibility genes of schizophrenia. However, little is known about the underlying mechanisms of their malfunction. Although ErbB4 is enriched in GABAergic interneurons, the role of NRG1 in excitatory synapse formation in these neurons remains poorly understood. We showed that NRG1 increased both the number and size of PSD-95 puncta and the frequency and amplitude of miniature EPSCs (mEPSCs) in GABAergic interneurons, indicating that NRG1 stimulates the formation of new synapses and strengthens existing synapses. In contrast, NRG1 treatment had no effect on either the number or size of excitatory synapses in glutamatergic neurons, suggesting its synaptogenic effect is specific to GABAergic interneurons. Ecto-ErbB4 treatment diminished both the number and size of excitatory synapses, suggesting that endogenous NRG1 may be critical for basal synapse formation. NRG1 could stimulate the stability of PSD-95 in the manner that requires tyrosine kinase activity of ErbB4. Finally, deletion of ErbB4 in parvalbumin-positive interneurons led to reduced frequency and amplitude of mEPSCs, providing in vivo evidence that ErbB4 is important in excitatory synaptogenesis in interneurons. Together, our findings suggested a novel synaptogenic role of NRG1 in excitatory synapse development, possibly via stabilizing PSD-95, and this effect is specific to GABAergic interneurons. In light of the association of the genes of both NRG1 and ErbB4 with schizophrenia and dysfunction of GABAergic system in this disorder, these results provide insight into its potential pathological mechanism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 263 | Transl Psychiatry 2011 -1 1: e8 |
| PMID | 22832403 |
| Title | Increased expression of receptor phosphotyrosine phosphatase-?/? is associated with molecular, cellular, behavioral and cognitive schizophrenia phenotypes. |
| Abstract | schizophrenia is a serious and chronic mental disorder, in which both genetic and environmental factors have a role in the development of the disease. Neuregulin-1 (NRG1) is one of the most established genetic risk factors for schizophrenia, and disruption of NRG1 signaling has been reported in this disorder. We reported previously that NRG1/ErbB4 signaling is inhibited by receptor phosphotyrosine phosphatase-?/? (RPTP ?/?) and that the gene encoding RPTP?/? (PTPRZ1) is genetically associated with schizophrenia. In this study, we examined the expression of RPTP?/? in the brains of patients with schizophrenia and observed increased expression of this gene. We developed mice overexpressing RPTP?/? (PTPRZ1-transgenic mice), which showed reduced NRG1 signaling, and molecular and cellular changes implicated in the pathogenesis of schizophrenia, including altered glutamatergic, GABAergic and dopaminergic activity, as well as delayed oligodendrocyte development. Behavioral analyses also demonstrated schizophrenia-like changes in the PTPRZ1-transgenic mice, including reduced sensory motor gating, hyperactivity and working memory deficits. Our results indicate that enhanced RPTP?/? signaling can contribute to schizophrenia phenotypes, and support both construct and face validity for PTPRZ1-transgenic mice as a model for multiple schizophrenia phenotypes. Furthermore, our results implicate RPTP?/? as a therapeutic target in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 264 | Mol. Psychiatry 2011 Mar 16: 307-20 |
| PMID | 20142818 |
| Title | Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia. |
| Abstract | Neuregulin-1 (NRG1) is implicated in the etiology or pathology of schizophrenia, although its biological roles in this illness are not fully understood. Human midbrain dopaminergic neurons highly express NRG1 receptors (ErbB4). To test its neuropathological role in the neurodevelopmental hypothesis of schizophrenia, we administered type-1 NRG1 protein to neonatal mice and evaluated the immediate and subsequent effects on dopaminergic neurons and their associated behaviors. Peripheral NRG1 administration activated midbrain ErbB4 and elevated the expression, phosphorylation and enzyme activity of tyrosine hydroxylase (TH), which ultimately increased dopamine levels. The hyperdopaminergic state was sustained in the medial prefrontal cortex after puberty. There were marked increases in dopaminergic terminals and TH levels. In agreement, higher amounts of dopamine were released from this brain region of NRG1-treated mice following high potassium stimulation. Furthermore, NRG1-treated mice exhibited behavioral impairments in prepulse inhibition, latent inhibition, social behaviors and hypersensitivity to methamphetamine. However, there were no gross abnormalities in brain structures or other phenotypic features of neurons and glial cells. Collectively, our findings provide novel insights into neurotrophic contribution of NRG1 to dopaminergic maldevelopment and schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 265 | Int. J. Neuropsychopharmacol. 2011 Jun 14: 631-43 |
| PMID | 20701826 |
| Title | The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of cannabinoids. |
| Abstract | Cannabis increases the risk of schizophrenia in genetically vulnerable individuals. In this study we aim to show that the schizophrenia susceptibility gene neuregulin 1 (NRG1) modulates the development of tolerance to cannabinoids in mice. NRG1 heterozygous (HET) and wild-type (WT) mice were treated daily for 15 d with the synthetic analogue of ?9-tetrahydrocannabinol, CP55,940 (0.4 mg/kg). We measured the impact of this exposure on locomotor activity, anxiety, prepulse inhibition (PPI), body temperature and FosB/?FosB immunohistochemistry. Tolerance to CP55,940-induced hypothermia and locomotor suppression developed more rapidly in NRG1 HET mice than WT mice. Conversely in the light-dark test, while tolerance to the anxiogenic effect of CP55,940 developed in WT mice over days of testing, NRG1 hypomorphs maintained marked anxiety even after 15 d of treatment. Repeated cannabinoid exposure selectively increased FosB/?FosB expression in the lateral septum, ventral part (LSV) of NRG1 HET but not WT mice. On day 1 of exposure opposite effects of CP55,940 treatment were observed on PPI, i.e. it was facilitated in NRG1 hypomorphs and impaired in WT mice, despite the drug significantly impairing the acoustic startle reflex equally in both genotypes. These effects of CP55,940 on PPI were not maintained as both genotypes became tolerant to cannabinoid action with repeated exposure. Our results highlight that NRG1 modulates the development of cannabinoid tolerance dependent on the parameter being measured. Furthermore, these data reinforce the notion that the VLS is an important brain region involved in NRG1-cannabinoid interactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 266 | Cell J 2011 -1 13: 91-6 |
| PMID | 23508206 |
| Title | A Study of the Association between SNP8NRG241930 in the 5' End of Neuroglin 1 Gene with Schizophrenia in a Group of Iranian Patients. |
| Abstract | Neuregulin1 (NRG1) gene is among the most promising candidate genes for schizophrenia. This gene is located on 8p22-p12, a region with a reported linkage to schizophrenia. Several studies have reported an association between schizophrenia and the 5' end polymorphisms in this gene. However, some studies have failed to confirm the role of NRG1 gene in the pathogenesis of schizophrenia. In the current study, we attempt to examine the association of SNP8NRG241930 from the NRG1 gene with schizophrenia in an Iranian population. It is noteworthy that there has been no report on the NRG1 association with schizophrenia in a population from the Middle East region. Genomic DNA samples were obtained via isolation from the peripheral blood cells of 95 unrelated subjects with schizophrenia and 95 matched healthy controls from southwest Iran. SNP8NRG241930 was genotyped by PCRRFLP using ScaI as a restriction endonuclease enzyme. Association of the SNP with schizophrenia was examined using the chi-square test. The frequency difference of alleles and genotypes between the two groups were compared. P?0.05 was considered significant. Statistical analysis on the studied polymorphism showed that both case and control groups were in Hardy-Weinberg equilibrium. The frequency of high risk allele (G allele) was 72.6% in patients, while this number was 56.8% in controls. The genotype frequencies in the patient group were as follows: GG (54%), GT (38%) and TT (8%) vs. genotype frequencies in the control group of: GG (26%), GT (63 %) and TT (11%). Considering allele and genotype frequencies, a significant association was observed between schizophrenia and SNP8NRG241930. The current study adds weight to the idea that some functional polymorphisms could exist in the 5' end of the NRG1 gene which increase susceptibility to schizophrenia. This is the first time that supportive evidence shows an involvement of the NRG1 locus in schizophrenia in an Iranian sample population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 267 | J. Neurosci. 2011 Jun 31: 8491-501 |
| PMID | 21653853 |
| Title | Specific regulation of NRG1 isoform expression by neuronal activity. |
| Abstract | Neuregulin 1 (NRG1) is a trophic factor that has been implicated in neural development, neurotransmission, and synaptic plasticity. NRG1 has multiple isoforms that are generated by usage of different promoters and alternative splicing of a single gene. However, little is known about NRG1 isoform composition profile, whether it changes during development, or the underlying mechanisms. We found that each of the six types of NRG1 has a distinct expression pattern in the brain at different ages, resulting in a change in NRG1 isoform composition. In both human and rat, the most dominant are types III and II, followed by either type I or type V, while types IV and VI are the least abundant. The expression of NRG1 isoforms is higher in rat brains at ages of E13 and P5 (in particular type V), suggesting roles in early neural development and in the neonatal critical period. At the cellular level, the majority of NRG1 isoforms (types I, II, and III) are expressed in excitatory neurons, although they are also present in GABAergic neurons and astrocytes. Finally, the expression of each NRG1 isoform is distinctly regulated by neuronal activity, which causes significant increase in type I and IV NRG1 levels. Neuronal activity regulation of type IV expression requires a CRE cis-element in the 5' untranslated region (UTR) that binds to CREB. These results indicate that expression of NRG1 isoforms is regulated by distinct mechanisms, which may contribute to versatile functions of NRG1 and pathologic mechanisms of brain disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 268 | Behav. Brain Res. 2011 Oct 224: 223-32 |
| PMID | 21620900 |
| Title | Sex-specific neuroendocrine and behavioral phenotypes in hypomorphic Type II Neuregulin 1 rats. |
| Abstract | Neuregulin 1 (NRG1) is an important growth factor involved in the development and plasticity of the central nervous system. Since its identification as a susceptibility gene for schizophrenia, several transgenic mouse models have been employed to elucidate the role NRG1 may play in the pathogenesis of psychiatric disease. Unfortunately very few studies have included females, despite the fact that some work suggests that the consequences of disrupted NRG1 expression may be sex-specific. Here, we used NRG1 hypomorphic (NRG1(Tn)) Fischer rats to demonstrate sex-specific changes in neuroendocrine and behavioral phenotypes as a consequence of reduced Type II NRG1 expression. We have previously shown that male NRG1(Tn) rats have increased basal corticosterone levels, and fail to habituate to an open field despite normal overall levels of locomotor activity. The current studies show that, in contrast, female NRG1(Tn) rats exhibit enhanced suppression of corticosterone levels following an acute stress, reduced locomotor activity, and enhanced habituation to novel environments. Furthermore, we also show that female, but not male, NRG1(Tn) rats have impaired prepulse inhibition. Finally, we provide evidence that sex-specific changes are not likely attributable to major disruptions in the hypothalamic-pituitary-gonadal axis, as measures of pubertal onset, estrous cyclicity, and reproductive capacity were unaltered in female NRG1(Tn) rats. Our results provide further support for both the involvement of NRG1 in the control of hypothalamic-pituitary-adrenal axis function and the sex-specific nature of this relationship. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 269 | Behav. Brain Res. 2011 Oct 223: 336-41 |
| PMID | 21605597 |
| Title | Do transmembrane domain neuregulin 1 mutant mice exhibit a reliable sensorimotor gating deficit? |
| Abstract | Evidence suggests that the heterozygous transmembrane domain mutant mouse model for the schizophrenia candidate gene neuregulin 1 (NRG1 HET) exhibits a deficit in prepulse inhibition (PPI). However, not all mouse models for NRG1 exhibit PPI deficits. Thus, our study intended to clarify the severity of the initially described PPI deficit in NRG1 HET mice. For this, NRG1 mutant mice and wild type-like littermates of one breeding colony were tested for PPI in four different phenotyping facilities in Australia employing a variety of different PPI protocols with fixed and variable interstimulus intervals (ISIs). Testing mutant and wild type-like mice in three Australian phenotyping facilities using PPI protocols with variable ISIs revealed no effect of mutant transmembrane domain NRG1 on sensorimotor gating. Changes to the startle response and startle response habituation were site/protocol-specific. The employment of two different PPI protocols at the same phenotyping facility revealed a protocol-dependent and site-specific facilitation of PPI in NRG1 mutant mice compared to wild type-like mice. In conclusion, the often-noted PPI phenotype of the transmembrane domain NRG1 mutant mouse model is highly PPI protocol-specific and appears sensitive to the particular conditions of the test laboratory. Our study describes wild type-like PPI under most test conditions and across three different laboratories. The research suggests that analysing one of the alleged hallmarks of animal models for schizophrenia must be done carefully: to obtain reliable PPI data it seems necessary to use more than one particular PPI protocol. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 270 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Apr 156B: 340-5 |
| PMID | 21234898 |
| Title | A phenotype-based genetic association study reveals the contribution of neuregulin1 gene variants to age of onset and positive symptom severity in schizophrenia. |
| Abstract | By pure endpoint diagnosis of the disease, the risk of developing schizophrenia has been repeatedly associated with specific variants of the neuregulin1 (NRG1) gene. However, the role of NRG1 in the etiology of schizophrenia has remained unclear. Since NRG1 serves vital functions in early brain development of mice, we hypothesized that human NRG1 alleles codetermine developmentally influenced readouts of the disease: age of onset and positive symptom severity. We analyzed 1,071 comprehensively phenotyped schizophrenic/schizoaffective patients, diagnosed according to DSM-IV-TR, from the GRAS (Göttingen Research Association for schizophrenia) Data Collection for genetic variability in the Icelandic region of risk in the NRG1 gene. For the case-control analysis part of the study, we included 1,056 healthy individuals with comparable ethnicity. The phenotype-based genetic association study (PGAS) was performed on the GRAS sample. Instead of a risk constellation, we detected that several haplotypic variants of NRG1 were, unexpectedly, less frequent in the schizophrenic than in the control sample (mean OR=0.78, range between 0.68 and 0.85). In the PGAS we found that these "protective" NRG1 variants are specifically underrepresented in subgroups of schizophrenic subjects with early age of onset and high positive symptom load. The GRAS Data Collection as a prerequisite for PGAS has enabled us to associate protective NRG1 genotypes with later onset and milder course of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 271 | Physiol. Behav. 2011 Aug 104: 205-14 |
| PMID | 21092742 |
| Title | Disruption of the neuregulin 1 gene in the rat alters HPA axis activity and behavioral responses to environmental stimuli. |
| Abstract | Exposure to stress can result in an increased risk for psychiatric disorders, especially among genetically predisposed individuals. Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia and is also associated with psychotic bipolar disorder. In the rat, the neurons of the hypothalamic paraventricular nucleus show strong expression of NRG1 mRNA. In patients with schizophrenia, a single nucleotide polymorphism in the 5' region of NRG1 interacts with psychosocial stress to affect reactivity to expressed emotion. However, there is virtually no information on the role of NRG1 in hypothalamic-pituitary-adrenal axis function, and whether the protein is expressed in the paraventricular nucleus is unknown. The present studies utilize a unique line of NRG1 hypomorphic rats (NRG1(Tn)) generated by gene trapping with the Sleeping Beauty transposon. We first established that the NRG1(Tn) rats displayed reduced expression of both the mRNA and protein corresponding to the Type II NRG1 isoform. After confirming, using wild type animals, that Type II NRG1 is expressed in the neurocircuitry involved in regulating hypothalamic-pituitary-adrenal axis responses to environmental stimuli, the NRG1(Tn) rats were then used to test the hypothesis that altered expression of Type II NRG1 disrupts stress regulation and reactivity. In support of this hypothesis, NRG1(Tn) rats have disrupted basal and acute stress recovery corticosterone secretion, differential changes in expression of glucocorticoid receptors in the pituitary, paraventricular nucleus and hippocampus, and a failure to habituate to an open field. Together, these findings point to NRG1 as a potential novel regulator of neuroendocrine responses to stress as well as behavioral reactivity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 272 | Biol. Psychiatry 2011 Mar 69: 479-86 |
| PMID | 21035784 |
| Title | The influence of schizophrenia-related neuregulin-1 polymorphisms on sensorimotor gating in healthy males. |
| Abstract | Neuregulin-1 (NRG1) variations have been shown to modulate schizophrenia candidate endophenotypes related to brain structure and function. The objective of this cross-sectional genetic association study was to determine the relationship of six core single-nucleotide polymorphisms within the NRG1 gene identified as promising schizophrenia risk genes (rs6994992, SNP8NRG221132, SNP8NRG241930, rs3924999, rs2439272 and rs10503929) to prepulse inhibition (PPI) of the acoustic startle reflex, a well validated schizophrenia endophenotype. PPI was tested in a highly homogeneous study entry cohort (n = 445) of carefully screened healthy, young male army conscripts originating from the Greek LOGOS project (Learning on Genetics of schizophrenia Spectrum). The QTPHASE from the UNPHASED package was used for the association analysis of each single-nucleotide polymorphisms or haplotype data. Reduced PPI, particularly at 75-dB_120-msec and 85-dB_60-msec trials, was related to the SNP8NRG241930 G allele and especially the rs6994992 T allele and rs2439272 C allele. Haplotype analysis followed up by risk versus no-risk groups Analysis of variance confirmed that the rs10503929 and rs3924999 SNPs were also associated with PPI reductions, when combined with rs2439272. We provide solid evidence for a role of NRG1 risk genotype variations in PPI reductions in a large and demographically and genetically highly homogeneous cohort of healthy young males. These results further validate NRG1 as a candidate gene for the schizophrenia and spectrum disorders and improve our understanding of its functional mechanisms within the human brain because they suggest an influence of the gene in the neural substrate mediating sensorimotor gating. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 273 | Neuropsychopharmacology 2011 Jan 36: 488-96 |
| PMID | 20927045 |
| Title | Disrupted activity in the hippocampal-accumbens circuit of type III neuregulin 1 mutant mice. |
| Abstract | Neuregulin 1 (NRG1), a schizophrenia susceptibility gene, is involved in fundamental aspects of neurodevelopment. Mice lacking any one of the several isoforms of NRG1 have a variety of schizophrenia-related phenotypes, including deficits in working memory and sensorimotor gating, loss of spines in pyramidal neurons in the ventral subiculum, loss of dendrites in cortical pyramidal cells, loss of parvalbumin-positive interneurons in the prefrontal cortex, and altered plasticity in corticolimbic synapses. Mice heterozygous for a disruption in exon 7 of the NRG1 gene lack Type III (cysteine-rich-domain-containing) isoforms and have sensorimotor gating deficits that may involve changes in the activity of a circuit involving projections from the ventral hippocampus (vHPC) to medium spiny neurons in the nucleus accumbens (nACC). To explore the neural basis of these deficits, we examined electrophysiological activity in the nACC and vHPC of these mice. Under urethane anesthesia, bursts of spontaneous activity propagated from the vHPC to the nACC in both wild-type and mutant mice. However, these bursts were weaker in mutant nACC, with reduced local field potential amplitude and spiking activity. Single units in mutant nACC fired less frequently within the bursts, and more frequently outside of the bursts. Moreover, within-burst nACC spiking was less modulated by vHPC activity, as determined by phase-locking to the low-frequency oscillatory components of the bursts. These data suggest that the efficacy of vHPC input to the nACC is reduced in the Type III NRG1 heterozygotes, supporting a role for NRG1 in the functional profile of hippocampal-accumbens synapses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 274 | Schizophr Bull 2011 Jul 37: 822-31 |
| PMID | 19965935 |
| Title | Schizophrenia-related neuregulin-1 single-nucleotide polymorphisms lead to deficient smooth eye pursuit in a large sample of young men. |
| Abstract | Neuregulin-1 (NRG1) variations have been shown to modulate schizophrenia candidate endophenotypes related to brain structure and function. The aim of this study was to determine the effect of NRG1 on several oculomotor schizophrenia endophenotypes. The effects of 5 core single-nucleotide polymorphisms (SNPs) within the NRG1 gene to oculomotor parameters in a battery of oculomotor tasks (saccade, antisaccade, smooth eye pursuit, fixation) were investigated in a sample of 2243 young male military conscripts. Additive regression models, bootstrap and permutation techniques, were used as well as structural equation modeling and haplotype analysis. A deficit in global smooth eye pursuit performance measured using the root-mean-square error (RMSE) was related to the risk allele of SNP8NRG243177, and a deficit in global smooth eye pursuit performance measured using the saccade frequency was related with the risk allele of SNP8NRG433E1006. Structural equation modeling confirmed a global effect of NRG1 genotype on smooth eye pursuit performance using the RMSE, while the effect on saccade frequency was not confirmed. Haplotype analysis further confirmed the prediction from the structural equation modeling that a combination of alleles corresponding to the Icelandic high-risk haplotype was related to a deficit in global pursuit performance. NRG1 genotype variations were related to smooth eye pursuit variations both at the SNP level and at the haplotype level adding to the validation of this gene as a candidate gene for the disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 275 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Jun 35: 924-30 |
| PMID | 21513767 |
| Title | Antipsychotic treatment and neuregulin 1-ErbB4 signalling in schizophrenia. |
| Abstract | Evidence from genetic, transgenic and post-mortem studies has strongly supported the critical role that neuregulin 1 (NRG1) and its ErbB4 receptor plays in the pathophysiology of schizophrenia. This article aims to review current evidence regarding the effects of antipsychotic treatment on NRG1-ErbB4 signalling. NRG1 and ErbB4 knockout mice display abnormal behaviours relevant to certain features of schizophrenia, which could be improved by antipsychotic (clozapine/haloperidol) treatment. In contrast to most NRG1/ErbB4 knockout mice with a decreased NRG1-ErbB4 signalling, the majority post-mortem studies showed an increased NRG1-ErbB4 signalling in schizophrenic patients. These differences could be due to degrees of alteration in risk genes (subtle variations in patients vs pronounced alteration in mutant mice) or the duration of the modification on NRG1 signalling. Various antipsychotics have different effects on NRG1 and ErbB4 expression and signalling that are dependent on treatment duration. Current evidence suggests that a chronic (12weeks) antipsychotic treatment, at least in animal models, could downregulate NRG1-ErbB4 signalling, although an upregulation is seen for a short-term treatment. These effects may be due to multiple binding profiles with various G-coupled protein receptors (e.g. dopamine, and serotonin receptors) of antipsychotics. Studies are needed to investigate the interactions between NRG1-ErbB4 and the other signalling pathways (such as glutamatergic, GABAergic and dopaminergic). Furthermore, the interactions between NRG1/ErbB4 and other schizophrenia suspensibility genes under antipsychotic treatment also require investigation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 276 | Am J Psychiatry 2011 Sep 168: 930-46 |
| PMID | 21498463 |
| Title | Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia. |
| Abstract | The authors used a custom array of 1,536 single-nucleotide polymorphisms (SNPs) to interrogate 94 functionally relevant candidate genes for schizophrenia and identify associations with 12 heritable neurophysiological and neurocognitive endophenotypes in data collected by the Consortium on the Genetics of schizophrenia. Variance-component association analyses of 534 genotyped subjects from 130 families were conducted by using Merlin software. A novel bootstrap total significance test was also developed to overcome the limitations of existing genomic multiple testing methods and robustly demonstrate significant associations in the context of complex family data and possible population stratification effects. Associations with endophenotypes were observed for 46 genes of potential functional significance, with three SNPs at p<10(-4), 27 SNPs at p<10(-3), and 147 SNPs at p<0.01. The bootstrap analyses confirmed that the 47 SNP-endophenotype combinations with the strongest evidence of association significantly exceeded that expected by chance alone, with 93% of these findings expected to be true. Many of the genes interact on a molecular level, and eight genes (e.g., NRG1 and ERBB4) displayed evidence for pleiotropy, revealing associations with four or more endophenotypes. The results collectively support a strong role for genes related to glutamate signaling in mediating schizophrenia susceptibility. This study supports use of relevant endophenotypes and the bootstrap total significance test for identifying genetic variation underlying the etiology of schizophrenia. In addition, the observation of extensive pleiotropy for some genes and singular associations for others suggests alternative, independent pathways mediating pathogenesis in the "group of schizophrenias." |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 277 | Neurosci. Res. 2011 Jun 70: 155-63 |
| PMID | 21352860 |
| Title | The ERBB4 intracellular domain (4ICD) regulates NRG1-induced gene expression in hippocampal neurons. |
| Abstract | The NRG1 growth factor and ERBB4 receptor have been identified as leading schizophrenia risk genes. Although NRG1 and ERBB4 have been shown to modulate neuronal functions involved in schizophrenia, including both GABAergic and glutamatergic synapses, the exact molecular mechanisms remain poorly understood. Here we investigated ERBB4 intracellular domain, 4ICD, transactivator function in rat hippocampal cultures by inhibiting ?-secretase mediated ERBB4 regulated intramembrane proteolysis (RIP). NRG1 stimulation resulted in a dramatic increase in the number of hippocampal cells displaying nuclear 4ICD which was abolished in cultures pretreated with the ?-secretase inhibitor compound E (CE). To identify NRG1-4ICD transactivated genes we compared global gene expression profiles of hippocampal cultures stimulated with NRG1 in the absence or presence of CE. In concordance with the contribution of NRG1-ERBB4 signaling to dendritic spine maturation and schizophrenia, global gene expression analysis followed by Ingenuity Pathway Analysis of the dataset identified NRG1-4ICD regulated genes significantly represented in semaphorin signaling and actin cytoskeletal plasticity and multiple genes with confirmed roles in dendritic spine morphogenesis. Using the power of global gene expression analysis our data provides a proof-of-concept supporting a role for non-canonical NRG1-4ICD signaling in the regulation of gene expression contributing to normal and schizophrenic neuronal function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 278 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Apr 156B: 340-5 |
| PMID | 21234898 |
| Title | A phenotype-based genetic association study reveals the contribution of neuregulin1 gene variants to age of onset and positive symptom severity in schizophrenia. |
| Abstract | By pure endpoint diagnosis of the disease, the risk of developing schizophrenia has been repeatedly associated with specific variants of the neuregulin1 (NRG1) gene. However, the role of NRG1 in the etiology of schizophrenia has remained unclear. Since NRG1 serves vital functions in early brain development of mice, we hypothesized that human NRG1 alleles codetermine developmentally influenced readouts of the disease: age of onset and positive symptom severity. We analyzed 1,071 comprehensively phenotyped schizophrenic/schizoaffective patients, diagnosed according to DSM-IV-TR, from the GRAS (Göttingen Research Association for schizophrenia) Data Collection for genetic variability in the Icelandic region of risk in the NRG1 gene. For the case-control analysis part of the study, we included 1,056 healthy individuals with comparable ethnicity. The phenotype-based genetic association study (PGAS) was performed on the GRAS sample. Instead of a risk constellation, we detected that several haplotypic variants of NRG1 were, unexpectedly, less frequent in the schizophrenic than in the control sample (mean OR=0.78, range between 0.68 and 0.85). In the PGAS we found that these "protective" NRG1 variants are specifically underrepresented in subgroups of schizophrenic subjects with early age of onset and high positive symptom load. The GRAS Data Collection as a prerequisite for PGAS has enabled us to associate protective NRG1 genotypes with later onset and milder course of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 279 | Curr. Pharm. Des. 2012 -1 18: 5024-35 |
| PMID | 22716151 |
| Title | Gene-environment interactions underlying the effect of cannabis in first episode psychosis. |
| Abstract | Cannabis use may be considered as an additional risk factor in a diathesis-stress model of schizophrenia where the risk of developing the illness would be higher in genetic vulnerable people. In this regard, much of the research on cannabis and psychosis is currently focusing on gene-environment interactions. The present review will focus on the interaction between genes and cannabis exposure in the development of psychotic symptoms and schizophrenia and the biological mechanisms of cannabis. Cannabis use has been shown to act together with other environmental factors such as childhood trauma or urbanicity producing synergistic dopamine sensitization effects. Studies on gene-environment interaction have mainly included genetic variants involved in the regulation of the dopaminergic system. The most promising genetic variants in this field are COMT, CNR1, BDNF, AKT1 and NRG1. Additionally, the interaction with other environmental factors and possible gene-gene interactions are considered in the etiological model. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 280 | Integr Biol (Camb) 2012 Sep 4: 1096-101 |
| PMID | 22777684 |
| Title | The severity of mental disorders is linked to interaction among candidate genes. |
| Abstract | There is a considerable overlap in the manifestation of symptoms in three mental disorders namely unipolar disorder, bipolar disorder and schizophrenia. A gene coexpression network was developed based on a mutual information approach including four candidate genes (NRG1, DISC1, BDNF and COMT) along with other coexpressing genes in unipolar disorder, bipolar disorder and schizophrenia. There is a significant difference in the degree distribution of nodes between normal and bipolar disorder network and bipolar disorder network and schizophrenia network. Moreover, there is a differential direct connectivity among candidate genes in various mental disorders and between normal and mental disorders. All candidate genes are directly connected to each other in schizophrenia except one pair (NRG1-BDNF) indicating a strong role of inter-gene interactions in the manifestation of severe symptoms in this disease. DISC1 and NRG1 are key hub genes in the unipolar disorder network and the bipolar disorder network but have lost the role of hub genes in schizophrenia network, despite their significant association with schizophrenia. This study indicates that the three psychiatric diseases may not have discrete classes but three phenotypic manifestations of the same continuous disease based on severity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 281 | Scientifica (Cairo) 2012 -1 2012: 560514 |
| PMID | 24278715 |
| Title | The Association between COMT, BDNF, and NRG1 and Premorbid Social Functioning in Patients with Psychosis, Their Relatives, and Controls. |
| Abstract | We investigated the influences of putative candidate genes for psychosis on premorbid social adjustment and on premorbid schizoid-schizotypal traits. A family-based sample was used including 177 patients with schizophrenia or bipolar I disorder with a history of psychotic symptoms, 86 of their unaffected relatives, and 116 unrelated healthy controls. Association analyses on the combined sample were conducted using the Statistical Analysis for Genetic Epidemiology software (SAGE) and adjusting for age, sex, clinical group, and the family-based nature of the data. The COMT Val(158)Met and BDNF Val(66)Met polymorphisms showed no evidence of association with either phenotype. The SNP rs221533 of the NRG1 gene was significantly associated with premorbid adjustment in adolescence with TT homozygous subjects having a poorer performance than C allele carriers. In the context of neurodevelopmental disorders such as schizophrenia and other psychoses, this finding is plausible; however, it is preliminary and requires replication in an independent sample. In a broader sense, the use of intermediate quantitative phenotypes such as the ones presented in this study may be of help to understand the mechanism of action of genetic risk factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 282 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Jan 36: 17-21 |
| PMID | 21993442 |
| Title | Analysis of association between common SNPs in ErbB4 and bipolar affective disorder, major depressive disorder and schizophrenia in the Han Chinese population. |
| Abstract | Neuregulin-1 (NRG1) is associated with schizophrenia. As one of the receptors of NRG1, v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) has also been reported to be associated with schizophrenia. Since there can be shared genetic variants among bipolar affective disorder, major depressive disorder and schizophrenia, we tested the association between ErbB4 and these three major psychiatric disorders in the Han Chinese population. Five single nucleotide polymorphisms (SNPs) were selected based on previous positive reports and linkage disequilibrium information of the HapMap Han Chinese individuals from Beijing (CHB)+individuals from Tokyo, Japan (JPT) population. These SNPs were genotyped in 1140 bipolar affective disorder (BPAD) patients, 1140 schizophrenia (SCZ) patients, 1139 major depressive disorder (MDD) patients and 1140 normal controls. Two SNPs (rs707284 and rs839523) showed nominal significance in the BPAD patients but this was eliminated after permutation. No significant association between ErbB4 and the two other psychiatric disorders was observed, nor did haplotype analysis reveal any positive signal. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 283 | Exp Neurobiol 2012 Dec 21: 158-63 |
| PMID | 23319876 |
| Title | Association between a Missense Polymorphism (rs3924999, Arg253Gln) of Neuregulin 1 and Schizophrenia in Korean Population. |
| Abstract | Neuregulin 1 (NRG1) is associated with the pathogenesis of schizophrenia through controlling activation and signaling of neurotransmitter receptors. Influence to schizophrenia development by the NRG1 gene may differ in individuals, and genetic polymorphism is one of the factors affecting their differences. Association between three single nucleotide polymorphisms (SNPs) (rs7014762, -1174 A/T; rs11998176, -788 A/T; rs3924999, Arg253Gln) of NRG1 and the development of schizophrenia was analyzed in 221 schizophrneia and 359 control subjects. Polymerase chain reaction and direct sequencing were performed to obtain genotype data of NRG1 SNPs of the subjects. In analysis of genetic data, multiple logistic regression models (codominant1, codominant2, dominant, recessive, and log-additive model) were applied. SNPStats and SPSS 18.0 were used to calculate odds ratio (OR), 95% confidence interval (CI), and p-value of each model. The genotype distributions of rs3924999 were associated with schizophrenia development (OR=0.67, 95% CI=0.47-0.95, p=0.022 in the dominant model and OR=0.69, 95% CI=0.51-0.93, p=0.013 in the log-addtive model) and allelic distributions also showed significant association (OR=0.70, 95% CI=0.52-0.93, p=0.014). The results suggest that rs3924999 of the NRG1 gene may be associated with schizophrenia susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 284 | Neurosci. Lett. 2012 Dec 531: 131-5 |
| PMID | 23098760 |
| Title | The involvement of Type II Neuregulin-1 in rat visuospatial learning and memory. |
| Abstract | The cognitive deficits observed in schizophrenia are considered a core feature of the disease. Neuregulin-1 is a risk gene for schizophrenia that is involved in many neurodevelopmental and synaptic plasticity-related processes relevant to schizophrenia. Here, we have utilized a rat model (NRG1(Tn)), which is hypomorphic for the neuregulin-1 (NRG1) gene, to test whether reduced Type II NRG1 in the rat brain leads to cognitive deficits relevant to schizophrenia. Wild-type and homozygous NRG1(Tn) male rats were tested in memory tasks that evaluated spatial memory (Morris water maze) and visuospatial working and reference memory (Can Test). NRG1(Tn) rats were not impaired on the Morris water maze, but did show a deficit in the appetitive visuospatial discrimination test. NRG1(Tn) rats committed more reference and working memory errors in this test. These results indicate that decreased Type II NRG1 in the brain may lead to deficits in visuospatial learning and memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 285 | Neurosci. Lett. 2012 Apr 515: 82-6 |
| PMID | 22450046 |
| Title | The response of neuregulin 1 mutant mice to acute restraint stress. |
| Abstract | Stress plays a role in the development and severity of psychotic symptoms and there may be a genetic component to stress vulnerability in schizophrenia. Using an established mouse model for schizophrenia, we investigated the behavioural and endocrine response of NRG1 transmembrane domain mutant mice (NRG1 HET) and wild type-like (WT) littermates to acute restraint stress. Animals were screened at 3-4 months and 6-7 months of age (before and after onset of hyperlocomotion) for open field behaviour and serum corticosterone levels. In younger mice, stress reduced locomotive and explorative measures and increased anxiety-like behaviour regardless of genotype. Older NRG1 mutants were less susceptible to the effects of stress on anxiety-related behaviours. All mice responded to restraint stress with robust increases in serum corticosterone. Importantly, the stress-induced increase in corticosterone was more pronounced in NRG1 mutant than WT mice at the younger but not the older age. Our results suggest that transmembrane domain NRG1 has only a moderate effect on the acute stress response of mice. The behavioural differences detected between WT and NRG1 HET mice at the older age were evident without parallel modifications to the glucocorticoid system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 286 | Cereb. Cortex 2012 Jul 22: 1520-9 |
| PMID | 21878485 |
| Title | Transgenic overexpression of the type I isoform of neuregulin 1 affects working memory and hippocampal oscillations but not long-term potentiation. |
| Abstract | Neuregulin 1 (NRG1) is a growth factor involved in neurodevelopment and plasticity. It is a schizophrenia candidate gene, and hippocampal expression of the NRG1 type I isoform is increased in the disorder. We have studied transgenic mice overexpressing NRG1 type I (NRG1(tg-type I)) and their wild-type littermates and measured hippocampal electrophysiological and behavioral phenotypes. Young NRG1(tg-type I) mice showed normal memory performance, but in older NRG1(tg-type I) mice, hippocampus-dependent spatial working memory was selectively impaired. Hippocampal slice preparations from NRG1(tg-type I) mice exhibited a reduced frequency of carbachol-induced gamma oscillations and an increased tendency to epileptiform activity. Long-term potentiation in NRG1(tg-type I) mice was normal. The results provide evidence that NRG1 type I impacts on hippocampal function and circuitry. The effects are likely mediated via inhibitory interneurons and may be relevant to the involvement of NRG1 in schizophrenia. However, the findings, in concert with those from other genetic and pharmacological manipulations of NRG1, emphasize the complex and pleiotropic nature of the gene, even with regard to a single isoform. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 287 | Mol. Psychiatry 2012 Jan 17: 1, 99-107 |
| PMID | 21483438 |
| Title | Control of interneuron dendritic growth through NRG1/erbB4-mediated kalirin-7 disinhibition. |
| Abstract | Neuregulin 1 (NRG1) is a secreted trophic factor that activates the postsynaptic erbB4 receptor tyrosine kinase. Both NRG1 and erbB4 have been repeatedly associated with schizophrenia, but their downstream targets are not well characterized. ErbB4 is highly abundant in interneurons, and NRG1-mediated erbB4 activation has been shown to modulate interneuron function, but the role for NRG1-erbB4 signaling in regulating interneuron dendritic growth is not well understood. Here we show that NRG1/erbB4 promote the growth of dendrites in mature interneurons through kalirin, a major dendritic Rac1-GEF. Recent studies have shown associations of the KALRN gene with schizophrenia. Our data point to an essential role of phosphorylation in kalirin-7's C terminus as the critical site for these effects. As reduced interneuron dendrite length occurs in schizophrenia, understanding how NRG1-erbB4 signaling modulates interneuron dendritic morphogenesis might shed light on disease-related alterations in cortical circuits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 288 | Mol. Psychiatry 2012 Sep 17: 887-905 |
| PMID | 22584867 |
| Title | Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. |
| Abstract | We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 289 | J Psychiatr Res 2012 Mar 46: 279-84 |
| PMID | 22209534 |
| Title | Hippocampal volume and the AKT signaling system in first-episode schizophrenia. |
| Abstract | The phosphoinositide 3'-kinase (PI3K)--protein kinase B (AKT1)--glycogen synthase kinase (GSK)-3? system is modulated by several factors implicated in the pathophysiology of schizophrenia. Evidence suggests that neuregulin 1 (NRG1) induces decreased AKT phosphorylation in schizophrenia relative to healthy controls, which may be related to dysfunctional neurodevelopment and neuroplasticity. The aim of this study was to investigate the relationship between NRG1--induced AKT phosphorylation and hippocampal volume in schizophrenia. Participants were 20 first-episode patients with schizophrenia who did not receive psychotropic medications and 20 matched healthy controls. We measured the phosphorylated AKT--total AKT and phosphorylated ERK (extracellular signal-regulated kinase)--total ERK ratios in peripheral lymphoblasts before and after NRG1 administration. Whole-brain, left, and right hippocampal volumes were quantified using FreeSurfer software. Patients with schizophrenia displayed decreased AKT but normal ERK ratio compared with controls. Patients also had a reduction in left hippocampal volume. There was no significant difference between patients and controls in whole-brain and right hippocampal volume. Decreased AKT ratio was associated with reduced hippocampal volume. There was no significant relationship between ERK ratio and brain structure. Activation of the AKT system is specifically associated with hippocampal volume in first-episode schizophrenia, which provides further evidence for the pivotal role of this messenger system in the pathophysiology of psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 290 | Eur Neuropsychopharmacol 2012 Aug 22: 596-606 |
| PMID | 22264868 |
| Title | Characterization of the neuropsychological phenotype of glycine N-methyltransferase-/- mice and evaluation of its responses to clozapine and sarcosine treatments. |
| Abstract | Glycine N-methyltransferase (GNMT) affects cellular methylation capacity through regulating the ratio between S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). The product of its enzymatic reaction-sarcosine has antipsychotic effect in patients with schizophrenia. In this study, through RT-PCR and immunohistochemical staining, we demonstrated that GNMT expressed in various neurons located in the cerebral cortex, hippocampus, substantia nigra and cerebellum. Compared to the wild-type mice, Gnmt-/- mice had significantly lower level of sarcosine in the cerebral cortex. Real-time PCR identified genes involved in the methionine metabolism (Dnmt1 and Dnmt3a), ErbB (NRG1 and ErbB4) and mTOR (Akt2, S6, S6k1 and S6k2) signaling pathways were dysregulated significantly in the cortex of Gnmt-/- mice. Acoustic startle reflex test demonstrated that Gnmt-/- mice had significantly lower level of prepulse inhibition and the deficit was ameliorated through clozapine or sarcosine treatment. Furthermore, liver-specific-human-GNMT transgenic with Gnmt-/- (Tg-GNMT/Gnmt-/-) mice were used to rule out that the phenotype was due to abnormal liver function. In summary, the neuropsychological abnormalities found in Gnmt-/- mice may represent an endophenotype of schizophrenia. GNMT plays an important role in maintaining normal physiological function of brain and Tg-GNMT/Gnmt-/- mice are useful models for development of therapeutics for patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 291 | Transl Psychiatry 2012 -1 2: e104 |
| PMID | 22832904 |
| Title | Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity. |
| Abstract | Excitement and controversy have followed neuregulin (NRG1) since its discovery as a putative schizophrenia susceptibility gene; however, the mechanism of action of the associated risk haplotype (HapICE) has not been identified, and specific genetic variations, which may increase risk to schizophrenia have remained elusive. Using a postmortem brain cohort from 37 schizophrenia cases and 37 controls, we resequenced upstream of the type I-IV promoters, and the HapICE repeat regions in intron 1. Relative abundance of seven NRG1 mRNA transcripts in the prefrontal cortex were determined and compared across diagnostic and genotypic groups. We identified 26 novel DNA variants and showed an increased novel variant load in cases compared with controls (?(2)=7.815; P=0.05). The average nucleotide diversity (? = 10.0 × 10(-4)) was approximately twofold higher than that previously reported for BDNF, indicating that NRG1 may be particularly prone to genetic change. A greater nucleotide diversity was observed in the HapICE linkage disequilibrium block in schizophrenia cases (?((case)) = 13.2 × 10(-4); ?((control)) = 10.0 × 10(-4)). The specific HapICE risk haplotype was associated with increased type III mRNA (F = 3.76, P = 0.028), which in turn, was correlated with an earlier age of onset (r = -0.343, P = 0.038). We found a novel intronic five-SNP haplotype ~730?kb upstream of the type I promoter and determined that this region functions as transcriptional enhancer that is suppressed by SRY. We propose that the HapICE risk haplotype increases expression of the most brain-abundant form of NRG1, which in turn, elicits an earlier clinical presentation, thus providing a novel mechanism through which this genetic association may increase risk of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 292 | Brain Behav. Immun. 2012 May 26: 660-71 |
| PMID | 22426432 |
| Title | Phenotypic effects of repeated psychosocial stress during adolescence in mice mutant for the schizophrenia risk gene neuregulin-1: a putative model of gene × environment interaction. |
| Abstract | There is a paucity of animal models by which the contributions of environmental and genetic factors to the pathobiology of psychosis can be investigated. This study examined the individual and combined effects of chronic social stress during adolescence and deletion of the schizophrenia risk gene neuregulin-1 (NRG1) on adult mouse phenotype. Mice were exposed to repeated social defeat stress during adolescence and assessed for exploratory behaviour, working memory, sucrose preference, social behaviour and prepulse inhibition in adulthood. Thereafter, in vitro cytokine responses to mitogen stimulation and corticosterone inhibition were assayed in spleen cells, with measurement of cytokine and brain-derived neurotrophic factor (BDNF) mRNA in frontal cortex, hippocampus and striatum. NRG1 mutants exhibited hyperactivity, decreased anxiety, impaired sensorimotor gating and reduced preference for social novelty. The effects of stress on exploratory/anxiety-related parameters, spatial working memory, sucrose preference and basal cytokine levels were modified by NRG1 deletion. Stress also exerted varied effect on spleen cytokine response to concanavalin A and brain cytokine and BDNF mRNA expression in NRG1 mutants. The experience of psychosocial stress during adolescence may trigger further pathobiological features that contribute to the development of schizophrenia, particularly in those with underlying NRG1 gene abnormalities. This model elaborates the importance of gene × environment interactions in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 293 | Psychol Med 2012 Mar 42: 607-16 |
| PMID | 21854684 |
| Title | Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results. |
| Abstract | Candidate gene studies have been a key approach to the genetics of schizophrenia (SCZ). However, the results of these studies are confusing and no genes have been unequivocally implicated. The hypothesis-driven candidate gene literature can be appraised by comparison with the results of genome-wide association studies (GWAS). We describe the characteristics of hypothesis-driven candidate gene studies from the SZGene database, and use pathway analysis to compare hypothesis-driven candidate genes with GWAS results from the International schizophrenia Consortium (ISC). SZGene contained 732 autosomal genes evaluated in 1374 studies. These genes had poor statistical power to detect genetic effects typical for human diseases, assessed only 3.7% of genes in the genome, and had low marker densities per gene. Most genes were assessed once or twice (76.9%), providing minimal ability to evaluate consensus across studies. The ISC studies had 89% power to detect a genetic effect typical for common human diseases and assessed 79% of known autosomal common genetic variation. Pathway analyses did not reveal enrichment of smaller ISC p values in hypothesis-driven candidate genes, nor did a comprehensive evaluation of meta-hypotheses driving candidate gene selection (SCZ as a disease of the synapse or neurodevelopment). The most studied hypothesis-driven candidate genes (COMT, DRD3, DRD2, HTR2A, NRG1, BDNF, DTNBP1 and SLC6A4) had no notable ISC results. We did not find support for the idea that the hypothesis-driven candidate genes studied in the literature are enriched for the common genetic variation involved in the etiology of SCZ. Larger samples are required to evaluate this conclusion definitively. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 294 | J. Neurosci. 2012 Oct 32: 13889-95 |
| PMID | 23035098 |
| Title | Neuregulin directly decreases voltage-gated sodium current in hippocampal ErbB4-expressing interneurons. |
| Abstract | The Neuregulin 1 (NRG1)/ErbB4 signaling pathway has been genetically and functionally implicated in the etiology underlying schizophrenia, and in the regulation of glutamatergic pyramidal neuron function and plasticity. However, ErbB4 receptors are expressed in subpopulations of GABAergic interneurons, but not in hippocampal or cortical pyramidal neurons, indicating that NRG1 effects on principal neurons are indirect. Consistent with these findings, NRG1 effects on hippocampal long-term potentiation at CA1 pyramidal neuron synapses in slices are mediated indirectly by dopamine. Here we studied whether NRG/ErbB signaling directly regulates interneuron intrinsic excitability by pharmacologically isolating ErbB4-expressing neurons in rat dissociated hippocampal cultures, which lack dopaminergic innervation. We found that NRG1 acutely attenuates ErbB4-expressing interneuron excitability by depolarizing the firing threshold; neurons treated with the pan-ErbB inhibitor PD158780 or negative for ErbB4 were unaffected. These effects of NRG1 are primarily attributable to decreased voltage-gated sodium channel activity, as current density was attenuated by ?60%. In stark contrast, NRG1 had minor effects on whole-cell potassium currents. Our data reveal the direct actions of NRG1 signaling in ErbB4-expressing interneurons, and offer novel insight into how NRG1/ErbB4 signaling can impact hippocampal activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 295 | Biol. Psychiatry 2012 Oct 72: 637-44 |
| PMID | 22520967 |
| Title | Linkage analysis followed by association show NRG1 associated with cannabis dependence in African Americans. |
| Abstract | A genetic contribution to cannabis dependence (CaD) has been established but susceptibility genes for CaD remain largely unknown. We employed a multistage design to identify genetic variants underlying CaD. We first performed a genome-wide linkage scan for CaD in 384 African American (AA) and 354 European American families ascertained for genetic studies of cocaine and opioid dependence. We then conducted association analysis under the linkage peak, first using data from a genome-wide association study from the Study of Addiction: Genetics and Environment, followed by replication studies of prioritized single nucleotide polymorphisms (SNPs) in independent samples. We identified the strongest linkage evidence with CaD (logarithm of odds = 2.9) on chromosome 8p21.1 in AAs. In the association analysis of the Study of Addiction: Genetics and Environment sample under the linkage peak, we identified one SNP (rs17664708) associated with CaD in both AAs (odds ratio [OR] = 2.93, p = .0022) and European Americans (OR = 1.38, p = .02). This SNP, located at NRG1, a susceptibility gene for schizophrenia, was prioritized for further study. We replicated the association of rs17664708 with CaD in an independent AAs sample (OR = 2.81, p = .0068). The joint analysis of the two AA samples demonstrated highly significant association between rs17664708 and CaD with adjustment for either global (p = .00044) or local ancestry (p = .00075). Our study shows that NRG1 is probably a susceptibility gene for CaD, based on convergent evidence of linkage and replicated associations in two independent AA samples. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 296 | Transl Psychiatry 2012 -1 2: e167 |
| PMID | 23032943 |
| Title | The association of white matter volume in psychotic disorders with genotypic variation in NRG1, MOG and CNP: a voxel-based analysis in affected individuals and their unaffected relatives. |
| Abstract | We investigated the role of variation in putative psychosis genes coding for elements of the white matter system by examining the contribution of genotypic variation in three single-nucleotide polymorphisms (SNPs) neuregulin 1 (NRG1) SNP8NRG221533, myelin oligodendrocytes glycoprotein (MOG) rs2857766 and CNP (rs2070106) and one haplotype HAP(ICE) (deCODE) to white matter volume in patients with psychotic disorder and their unaffected relatives. Structural magnetic resonance imaging and blood samples for genotyping were collected on 189 participants including patients with schizophrenia (SZ) or bipolar I disorder (BDI), unaffected first-degree relatives of these patients and healthy volunteers. The association of genotypic variation with white matter volume was assessed using voxel-based morphometry in SPM5. The NRG1 SNP and the HAP(ICE) haplotype were associated with abnormal white matter volume in the BDI group in the fornix, cingulum and parahippocampal gyrus circuit. In SZ the NRG1 SNP risk allele was associated with lower white matter volume in the uncinate fasciculus (UF), right inferior longitudinal fasciculus and the anterior limb of the internal capsule. Healthy G-homozygotes of the MOG SNP had greater white matter volume in areas of the brainstem and cerebellum; this relationship was absent in those with a psychotic disorder and the unaffected relatives groups. The CNP SNP did not contribute to white matter volume variation in the diagnostic groups studied. Variation in the genes coding for structural and protective components of myelin are implicated in abnormal white matter volume in the emotion circuitry of the cingulum, fornix, parahippocampal gyrus and UF in psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 297 | Psychopharmacology (Berl.) 2012 Dec 224: 349-62 |
| PMID | 22700037 |
| Title | Fronto-temporal-mesolimbic gene expression and heritable differences in amphetamine-disrupted sensorimotor gating in rats. |
| Abstract | Differences in sensitivity to the prepulse inhibition (PPI)-disruptive effects of D2-family agonists in Sprague-Dawley (SD) vs. Long Evans (LE) rats are heritable, reflect differential activation of DA signaling in the nucleus accumbens (NAC), and are associated with differences in expression of specific NAC genes. These differences may inform us about the biology of PPI deficits in disorders such as schizophrenia. After confirming these strain-based PPI differences, we measured expression of four genes in NAC and other regions that regulate PPI: medial prefrontal cortex and ventral hippocampus (VH). Startle and PPI were assessed in SD and LE rats administered D-amphetamine (0 vs. 4.5 mg/kg, sc). Two weeks later, brain tissue was processed for comt, NRG1, grid2, and csnk1e expression; blood comt expression was also tested. Data confirmed expected PPI phenotypes. Gene expression levels differed across strains, sexes, and brain regions, with LE > SD expression in most genes and regions, and female > male expression for all NAC genes. Within any brain region, expression of the four genes was highly inter-correlated; across regions, correlations were less robust, reflecting distinct strain- or sex-based subgroups. PPI amphetamine sensitivity at 120 ms correlated significantly with NAC NRG1 expression, while amphetamine sensitivity for 30 ms PPI and startle magnitude correlated significantly with VH NRG1 and blood comt expression. Rat strains differing in a schizophrenia-linked phenotype also differ in expression levels of genes associated both with that phenotype, and with schizophrenia, within brain regions associated with that phenotype and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 298 | Curr Alzheimer Res 2012 Feb 9: 178-83 |
| PMID | 22455478 |
| Title | BACE1 dependent neuregulin processing: review. |
| Abstract | Neuregulin-1 (NRG1), known also as heregulin, acetylcholine receptor inducing activity (ARIA), glial growth factor (GGF), or sensory and motor neuron derived factor (SMDF), plays essential roles in several developmental processes, and is required also later in life. Many variants of NRG1 are produced via alternative splicing and usage of distinct promoters. All contain an epidermal growth factor (EGF)-like domain, which alone is sufficient to bind and activate the cognate receptors, members of the ErbB family. NRG1 mediated signaling is crucial for cardiogenesis and the development of the mammary gland and ErbB2 (HER2), an orphan co-receptor for NRG1 is the target of the drug Herceptin? (trastuzumab) used for treatment of metastatic breast cancer. In the nervous system, NRG1 controls the early development of subpopulations of neural crest cells. In particular, NRG1 acts as an essential paracrine signaling molecule expressed on the axonal surface, where it signals to Schwann cells throughout development and regulates the thickness of the myelin sheath. NRG1 is required also by other cell types in the nervous system, for instance as an axonal signal released by proprioceptive afferents to induce development of the muscle spindle, and it controls aspects of cortical interneuron development as well as the formation of thalamocortical projections. Work from several laboratories implicates dysregulation of NRG1/ErbB4 signaling in the etiology of schizophrenia. Biochemical studies have shown that the precursor proteins of NRG1 can be released from the membrane through limited proteolysis. In addition, most NRG1 isoforms contain a transmembrane domain, which is processed by ?-secretase after shedding. Thereby the intracellular domain is released into the cytoplasm. Despite this, the importance of NRG1 cleavage for its functions in vivo remained unclear until recently. ?- Secretase (?-site amyloid precursor protein cleaving enzyme 1, BACE1) was first identified through its function as the rate limiting enzyme of amyloid-?-peptide (A?) production. A? is the major component of amyloid plaques in Alzheimer's disease (AD). More recently it was shown that Neuregulin-1 is a major physiological substrate of BACE1 during early postnatal development. Mutant mice lacking BACE1 display severe hypomyelination of peripheral nerves similar to that seen in mice lacking NRG1/ErbB signaling in Schwann cells, and a BACE1-dependent activation of NRG1 in the process of peripheral myelination was proposed. Here we summarize the current knowledge about the role of NRG1 proteolysis for ErbB receptor mediated signaling during development and in Alzheimer's disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 299 | PLoS ONE 2012 -1 7: e44017 |
| PMID | 22952857 |
| Title | Allele-biased expression in differentiating human neurons: implications for neuropsychiatric disorders. |
| Abstract | Stochastic processes and imprinting, along with genetic factors, lead to monoallelic or allele-biased gene expression. Stochastic monoallelic expression fine-tunes information processing in immune cells and the olfactory system, and imprinting plays an important role in development. Recent studies suggest that both stochastic events and imprinting may be more widespread than previously considered. We are interested in allele-biased gene expression occurring in the brain because parent-of-origin effects suggestive of imprinting appear to play a role in the transmission of schizophrenia (SZ) and autism spectrum disorders (ASD) in some families. In addition, allele-biased expression could help explain monozygotic (MZ) twin discordance and reduced penetrance. The ability to study allele-biased expression in human neurons has been transformed with the advent of induced pluripotent stem cell (iPSC) technology and next generation sequencing. Using transcriptome sequencing (RNA-Seq) we identified 801 genes in differentiating neurons that were expressed in an allele-biased manner. These included a number of putative SZ and ASD candidates, such as A2BP1 (RBFOX1), ERBB4, NLGN4X, NRG1, NRG3, NRXN1, and NLGN1. Overall, there was a modest enrichment for SZ and ASD candidate genes among those that showed evidence for allele-biased expression (chi-square, p = 0.02). In addition to helping explain MZ twin discordance and reduced penetrance, the capacity to group many candidate genes affecting a variety of molecular and cellular pathways under a common regulatory process - allele-biased expression - could have therapeutic implications. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 300 | Proc. Natl. Acad. Sci. U.S.A. 2012 Jul 109: 12165-70 |
| PMID | 22689948 |
| Title | Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110? inhibition as a potential therapeutic strategy. |
| Abstract | Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in schizophrenia, but the mediating mechanisms are unknown. Here we identify a genetically regulated, pharmacologically targetable, risk pathway associated with schizophrenia and with ErbB4 genetic variation involving increased expression of a PI3K-linked ErbB4 receptor (CYT-1) and the phosphoinositide 3-kinase subunit, p110? (PIK3CD). In human lymphoblasts, NRG1-mediated phosphatidyl-inositol,3,4,5 triphosphate [PI(3,4,5)P3] signaling is predicted by schizophrenia-associated ErbB4 genotype and PIK3CD levels and is impaired in patients with schizophrenia. In human brain, the same ErbB4 genotype again predicts increased PIK3CD expression. Pharmacological inhibition of p110? using the small molecule inhibitor, IC87114, blocks the effects of amphetamine in a mouse pharmacological model of psychosis and reverses schizophrenia-related phenotypes in a rat neonatal ventral hippocampal lesion model. Consistent with these antipsychotic-like properties, IC87114 increases AKT phosphorylation in brains of treated mice, implicating a mechanism of action. Finally, in two family-based genetic studies, PIK3CD shows evidence of association with schizophrenia. Our data provide insight into a mechanism of ErbB4 association with schizophrenia; reveal a previously unidentified biological and disease link between NRG1-ErbB4, p110?, and AKT; and suggest that p110? is a previously undescribed therapeutic target for the treatment of psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 301 | Brain Res. 2012 Jul 1466: 146-51 |
| PMID | 22634065 |
| Title | Genetic association analysis of ERBB4 polymorphisms with the risk of schizophrenia and SPEM abnormality in a Korean population. |
| Abstract | The human receptor tyrosine-protein kinase erbB-4 (ERBB4) gene mediates neuregulin 1 (NRG1) signaling, and is involved in neuronal migration and differentiation. Despite the potential significance of ERBB4 in the development of schizophrenia, relatively few genetic studies for the association of ERBB4 with schizophrenia were performed in the populations including Ashkenazi Jews, Americans including Caucasians and African Americans, and Han Chinese. In this study, differences in ERBB4 variations were investigated to determine association with schizophrenia and smooth pursuit eye movement (SPEM) abnormality in a Korean population. Seven polymorphisms in ERBB4 gene were genotyped in 435 schizophrenia cases and 390 unrelated healthy controls. In order to investigate the relationship between ERBB4 and the risk of schizophrenia and SPEM abnormality, differences in SNP and haplotype distribution were analyzed using logistic and multiple regression analyses. However, we failed to replicate the associations reported by previous studies in other populations. Although statistically not significant, the tendency towards associations between ERBB4 polymorphisms and the risk of schizophrenia and SPEM abnormality in this study from a Korean population would be helpful for further genetic etiology studies in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 302 | Neuropsychopharmacology 2012 Aug 37: 2088-92 |
| PMID | 22549119 |
| Title | A common variant in ERBB4 regulates GABA concentrations in human cerebrospinal fluid. |
| Abstract | The neuregulin 1 (NRG1) receptor ErbB4 is involved in the development of cortical inhibitory GABAergic circuits and NRG1-ErbB4 signaling has been implicated in schizophrenia (SCZ). A magnetic resonance spectroscopy ((1)H-MRS) study has demonstrated that a single-nucleotide polymorphism in ERBB4, rs7598440, influences human cortical GABA concentrations. Other work has highlighted the significant impact of this genetic variant on expression of ERBB4 in the hippocampus and dorsolateral prefrontal cortex in human post mortem tissue. Our aim was to examine the association of rs7598440 with cerebrospinal fluid (CSF) GABA levels in healthy volunteers (n=155). We detected a significant dose-dependent association of the rs7598440 genotype with CSF GABA levels (G-allele standardized ?=-0.23; 95% CIs: -0.39 to -0.07; P=0.0066). GABA concentrations were highest in A homozygous, intermediate in heterozygous, and lowest in G homozygous subjects. When excluding subjects on psychotropic medication (three subjects using antidepressants), the results did not change (G-allele standardized ?=-0.23; 95% CIs: -0.40 to -0.07; P=0.0051). The explained variance in CSF GABA by rs7598440 in our model is 5.2% (P=0.004). The directionality of our findings agrees with the aforementioned (1)H-MRS and gene expression studies. Our observation therefore strengthens the evidence that the A-allele of rs7598440 in ERBB4 is associated with increased GABA concentrations in the human central nervous system (CNS). To our knowledge, our finding constitutes the first confirmation that CSF can be used to study genotype-phenotype correlations of GABA levels in the CNS. Such quantitative genetic analyses may be extrapolated to other CSF constituents relevant to SCZ in future studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 303 | PLoS ONE 2012 -1 7: e29630 |
| PMID | 22253750 |
| Title | Association analysis of 94 candidate genes and schizophrenia-related endophenotypes. |
| Abstract | While it is clear that schizophrenia is highly heritable, the genetic basis of this heritability is complex. Human genetic, brain imaging, and model organism studies have met with only modest gains. A complementary research tactic is to evaluate the genetic substrates of quantitative endophenotypes with demonstrated deficits in schizophrenia patients. We used an Illumina custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and evaluate association with both the qualitative diagnosis of schizophrenia and quantitative endophenotypes for schizophrenia. Subjects included 219 schizophrenia patients and normal comparison subjects of European ancestry and 76 schizophrenia patients and normal comparison subjects of African ancestry, all ascertained by the UCSD schizophrenia Research Program. Six neurophysiological and neurocognitive endophenotype test paradigms were assessed: prepulse inhibition (PPI), P50 suppression, the antisaccade oculomotor task, the Letter-Number Span Test, the California Verbal Learning Test-II, and the Wisconsin Card Sorting Test-64 Card Version. These endophenotype test paradigms yielded six primary endophenotypes with prior evidence of heritability and demonstrated schizophrenia-related impairments, as well as eight secondary measures investigated as candidate endophenotypes. schizophrenia patients showed significant deficits on ten of the endophenotypic measures, replicating prior studies and facilitating genetic analyses of these phenotypes. A total of 38 genes were found to be associated with at least one endophenotypic measure or schizophrenia with an empirical p-value<0.01. Many of these genes have been shown to interact on a molecular level, and eleven genes displayed evidence for pleiotropy, revealing associations with three or more endophenotypic measures. Among these genes were ERBB4 and NRG1, providing further support for a role of these genes in schizophrenia susceptibility. The observation of extensive pleiotropy for some genes and singular associations for others in our data may suggest both converging and independent genetic (and neural) pathways mediating schizophrenia risk and pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 304 | Eur Neuropsychopharmacol 2012 May 22: 356-63 |
| PMID | 21962913 |
| Title | Perinatal phencyclidine treatment alters neuregulin 1/erbB4 expression and activation in later life. |
| Abstract | schizophrenia is a complex and devastating mental disorder of unknown etiology. Hypofunction of N-methyl-D-aspartate (NMDA) receptors are implicated in the disorder, since phencyclidine (PCP) and other NMDA receptor antagonists mimic schizophrenia-like symptoms in humans and animals so well. Moreover, genetic linkage and post mortem studies strongly suggest a role for altered neuregulin 1 (NRG1)/erbB4 signaling in schizophrenia pathology. This study investigated the relationship between the NMDA receptor and NRG1 signaling pathways using the perinatal PCP animal model. Rats (n=5/group) were treated with PCP (10 mg/kg) or saline on postnatal days (PN) 7, 9 and 11 and were sacrificed on PN12, 5 weeks and 20 weeks for biochemical analyses. Western blotting was used to determine total and phosphorylated levels of proteins involved in NMDA receptor/NRG1 signaling in the prefrontal cortex and hippocampus. In the cortex, PCP treatment altered NRG1/erbB4 expression levels throughout development, including decreased NRG1 and erbB4 at PN12 (-25-30%; p<0.05); increased erbB4 and p-erbB4 (+18-27%; p<0.01) at 5 weeks; and decreased erbB4 and p-erbB4 (-16-18%; p<0.05) along with increased NRG1 (+33%; p<0.01) at 20 weeks. In the hippocampus, levels of NRG1/erbB4 were largely unaffected apart from a significant decrease in p-erbB4 at 20 weeks (-13%; p<0.001); however NMDA receptor subunits and PSD-95 showed increases at PN12 and 5 weeks (+20-32%; p<0.05), and decreases at 20 weeks (-22-29%; p<0.05). This study shows that NMDA receptor antagonism early in development can have long term effects on NRG1/erbB4 expression which could be important in understanding pathological processes which might be involved in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 305 | Mol. Psychiatry 2012 Nov 17: 1093-102 |
| PMID | 21876540 |
| Title | Statistical epistasis and progressive brain change in schizophrenia: an approach for examining the relationships between multiple genes. |
| Abstract | Although schizophrenia is generally considered to occur as a consequence of multiple genes that interact with one another, very few methods have been developed to model epistasis. Phenotype definition has also been a major challenge for research on the genetics of schizophrenia. In this report, we use novel statistical techniques to address the high dimensionality of genomic data, and we apply a refinement in phenotype definition by basing it on the occurrence of brain changes during the early course of the illness, as measured by repeated magnetic resonance scans (i.e., an 'intermediate phenotype.') The method combines a machine-learning algorithm, the ensemble method using stochastic gradient boosting, with traditional general linear model statistics. We began with 14 genes that are relevant to schizophrenia, based on association studies or their role in neurodevelopment, and then used statistical techniques to reduce them to five genes and 17 single nucleotide polymorphisms (SNPs) that had a significant statistical interaction: five for PDE4B, four for RELN, four for ERBB4, three for DISC1 and one for NRG1. Five of the SNPs involved in these interactions replicate previous research in that, these five SNPs have previously been identified as schizophrenia vulnerability markers or implicate cognitive processes relevant to schizophrenia. This ability to replicate previous work suggests that our method has potential for detecting a meaningful epistatic relationship among the genes that influence brain abnormalities in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 306 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Dec 39: 376-81 |
| PMID | 22850204 |
| Title | Adolescent neuregulin 1 heterozygous mice display enhanced behavioural sensitivity to methamphetamine. |
| Abstract | Methamphetamine use triggers psychosis in genetically vulnerable individuals, however the exact nature of this genetic predisposition requires elucidation. In addition, adolescence may be a particular period of neurodevelopmental vulnerability to the actions of methamphetamine; interestingly, this period coincides with a higher likelihood of onset of schizophrenia and drug experimentation. In the current study we investigated whether adolescent mice heterozygous for the schizophrenia susceptibility gene neuregulin 1 (NRG1 HET mice) exhibit altered behavioural responses to methamphetamine (0.6 or 2.4mg/kg) in schizophrenia-relevant paradigms. The responses measured were locomotor activity in the open field test and sensorimotor gating function in the prepulse inhibition of startle paradigm (PPI). Adolescent NRG1 HET mice displayed a subtle, transient, novelty-induced baseline locomotor hyperactivity over days, and a selective PPI deficit at the prepulse intensity-interstimulus interval (ISI) combination of 82dB-64ms. Adolescent NRG1 HET mice were more sensitive to the locomotor stimulatory effects of an acute, low-dose of methamphetamine (0.6mg/kg) relative to wild-type (WT) controls. The augmented response to acute methamphetamine observed in NRG1 HET mice disappeared with repeated, daily dosing over 7days. Methamphetamine did not affect average PPI (total or across different prepulse intensities), however 0.6mg/kg methamphetamine triggered a PPI deficit selectively in NRG1 HET mice but not WT mice at 82dB-256ms. Our results show that locomotor hyperactivity in NRG1 HET mice, albeit subtle, can manifest much earlier than previously reported and that NRG1 may confer vulnerability to the acute actions of methamphetamine, a drug known to trigger psychotic reactions in humans. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 307 | PLoS ONE 2012 -1 7: e36431 |
| PMID | 22590542 |
| Title | Differential neuregulin 1 cleavage in the prefrontal cortex and hippocampus in schizophrenia and bipolar disorder: preliminary findings. |
| Abstract | Neuregulin 1 (NRG1) is a key candidate susceptibility gene for both schizophrenia (SCZ) and bipolar disorder (BPD). The function of the NRG1 transmembrane proteins is regulated by cleavage. Alteration of membrane bound-NRG1 cleavage has been previously shown to be associated with behavioral impairments in mouse models lacking expression of NRG1-cleavage enzymes such as BACE1 and gamma secretase. We sought to determine whether alterations in NRG1 cleavage and associated enzymes occur in patients with SCZ and BPD. Using human postmortem brain, we evaluated protein expression of NRG1 cleavage products and enzymes that cleave at the external (BACE1, ADAM17, ADAM19) and internal (PS1-gamma secretase) sides of the cell membrane. We used three different cohorts (Controls, SCZ and BPD) and two distinct brain regions: BA9-prefrontal cortex (Controls (n = 6), SCZ (n = 6) and BPD (n = 6)) and hippocampus (Controls (n = 5), SCZ (n = 6) and BPD (n = 6)). In BA9, the ratio of the NRG1 N-terminal fragment relative to full length was significantly upregulated in the SCZ cohort (Bonferroni test, p = 0.011). ADAM17 was negatively correlated with full length NRG1 levels in the SCZ cohort (r = -0.926, p = 0.008). In the hippocampus we found significantly lower levels of a soluble 50 kDa NRG1 fragment in the two affected groups compared the control cohort (Bonferroni test, p = 0.0018). We also examined the relationship of specific symptomatology criteria with measures of NRG1 cleavage using the Bipolar Inventory of Signs and Symptoms Scale (BISS) and the Montgomery Åsberg Depression Rating Scale (MADRS). Our results showed a positive correlation between ADAM19 and psychosis (r = 0.595 p = 0.019); PS1 and mania (r = 0.535, p = 0.040); PS1 and depression (r = 0.567, p = 0.027) in BA9, and BACE1 with anxiety (r = 0.608, p = 0.03) in the hippocampus. Our preliminary findings suggest region-specific alterations in NRG1 cleavage in SCZ and BPD patients. These changes may be associated with specific symptoms in these psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 308 | PLoS ONE 2012 -1 7: e34129 |
| PMID | 22509273 |
| Title | Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice. |
| Abstract | The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (NRG1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, ?(9)-tetrahydrocannabinol. Here we investigated whether NRG1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male NRG1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. NRG1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT(2A) receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in NRG1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in NRG1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABA(A) receptor binding in the granular retrosplenial cortex in NRG1 TM HET mice and reduced 5-HT(2A) binding in the substantia nigra in WT mice. NRG1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that NRG1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 309 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jun 159B: 422-8 |
| PMID | 22467496 |
| Title | Association study of neuregulin 1 gene polymorphisms with auditory P300 in schizophrenia. |
| Abstract | Neuregulin 1 (NRG1), a gene involved with myelin production has been shown to have a positive correlation with schizophrenia. Event-related potentials (ERPs) studies provide the evidence of disturbed electrophysiologic marker in schizophrenia. The present study investigated the association of NRG1 genotypes with P300 in schizophrenia. Three polymorphisms in NRG1 gene were detected in 287 Chinese Han schizophrenics and 120 healthy control subjects. Among the total sample, 140 patients and 96 controls underwent P300. There were no significant differences for genotype distributions and allele frequencies between schizophrenic group and the control. A significant difference was observed between the schizophrenic patients and controls in the AT haplotype, with Odds Ratio 0.304 (P = 0.000882, 95% CI = 0.145-0.636). P300 amplitude in the schizophrenic group was significantly lower than that of the controls at Fz, Cz, Pz. P300 latency in the schizophrenic group was also significantly longer than that of the controls at Cz, Pz, Fz. Significant differences of P300 latency between three genotypes of rs3924999 were found at Cz and Pz both in schizophrenic group and the controls. The G/G carriers of rs3924999 tended to perform worse in the P300 latency as compared to A/A or A/G carriers both in the schizophrenia and controls. There were no significant differences for P300 latency and amplitude between schizophrenic group and controls for AT haplotype. NRG1 gene is a susceptible gene for Chinese Han schizophrenia and AT haplotype might have the protective role in the schizophrenia. Rs3924999 in NRG1 gene might functionally impact cognitive processing. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 310 | Neuropsychobiology 2012 -1 65: 119-25 |
| PMID | 22378022 |
| Title | Is neuregulin 1 involved in determining cerebral volumes in schizophrenia? Preliminary results showing a decrease in superior temporal gyrus volume. |
| Abstract | Reduced left superior temporal gyrus (STG) volume is one of the most replicated imaging findings in schizophrenia. However, it remains unclear whether genes play any role in our understanding of such structural alteration. It has been proposed that Neuregulin 1 (NRG1) might be a promising gene involved in schizophrenia, because of its role in neurodevelopment and neuroplasticity. In this study, the association between NRG1 and STG anatomy in patients with schizophrenia was explored for the first time. We investigated a 1-year treated prevalence cohort of patients with schizophrenia in contact with the South Verona Community-Based Mental Health Service. A blood sample was collected for DNA extraction and brain structure was assessed with an MRI scan. A total of 27 subjects with schizophrenia underwent both assessments and were included in the study. We investigated the association between the polymorphism SNP8NRG222662 (rs4623364) of NRG1 and volume of the STG. We found that patients homozygous for the C allele had reduced left STG gray and white matter volumes in comparison to those homozygous for the G allele (p < 0.01 and p < 0.001, respectively). This exploratory study suggests that NRG1 may be involved in determining STG size in schizophrenia, and may play a role in the neurogenetic basis of the language disturbances seen in this disorder. However, due to our small sample size, the results should be regarded as preliminary and replicated in a larger sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 311 | Psychiatr. Genet. 2012 Apr 22: 70-81 |
| PMID | 22183611 |
| Title | Genetic associations between neuregulin-1 SNPs and neurocognitive function in multigenerational, multiplex schizophrenia families. |
| Abstract | Recent work shows promising associations between schizophrenia and polymorphisms in neuregulin-1 (NRG1) and a large literature also finds strong familial relationships between schizophrenia and cognitive deficits. Given the role of NRG1 in glutamate regulation and glutamate's effect on cognition, we hypothesized that cognitive deficits may be related to variation within NRG1, providing a possible mechanism to increase risk for schizophrenia. This study examined the associations between NRG1, cognition, and schizophrenia using a multigenerational multiplex family sample (total N=419, 40 families), including 58 affected participants (schizophrenia or schizoaffective disorder-depressed type) and their 361 unaffected relatives. Participants were genotyped for 40 NRG1 single nucleotide polymorphisms (SNPs), chosen largely based on previous associations with schizophrenia. All participants completed structured diagnostic interviews and a computerized neurocognitive battery assessing eight cognitive domains. Variance component quantitative trait analyses tested for associations between individual NRG1 SNPs and cognitive performance in the total sample, a subsample of healthy participants with no Diagnostic and Statistical Manual of Mental Disorders diagnosis, and using general intelligence as a covariate. Effect sizes (within-family ? coefficients) ranged from 0.08 to 0.73, and 61 of these associations were nominally significant (P?0.05), with 12 associations at P?0.01, although none achieved the modified Bonferroni significance threshold of P<0.0003. Attention was the most frequently nominally associated domain and rs10503929, a nonsynonymous SNP, was the most frequently nominally associated SNP. Although not significant experiment-wise, these findings suggest that further study of the associations between variation in NRG1 and cognition may be productive. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 312 | Eur Arch Psychiatry Clin Neurosci 2012 Apr 262: 199-205 |
| PMID | 22120873 |
| Title | Case-control association study for 10 genes in patients with schizophrenia: influence of 5HTR1A variation rs10042486 on schizophrenia and response to antipsychotics. |
| Abstract | The aim of this study is to investigate possible associations between a set of single-nucleotide polymorphisms (SNPs) within 10 genes with schizophrenia (SCZ) and response to antipsychotics in Korean in-patients treated with antipsychotics. Two hundred and twenty-one SCZ in-patients and 170 psychiatrically healthy controls were genotyped for 42 SNPs within ABCB1, ABCB4, TAP2, CLOCK, CPLX1, CPLX2, SYN2, NRG1, 5HTR1A and GPRIN2. Baseline and final clinical measures, including the Positive and Negative Symptoms Scale (PANSS), were recorded. Rs10042486 within 5HTR1A was associated with both SCZ and clinical improvement on PANSS total scores as well as on PANSS positive and PANSS negative scores. The haplotype analyses focusing on the four, three and two blocks' haplotypes within 5HTR1A confirmed such findings as well. We did not observe any significant association between the remaining genetic variants under investigation in this study and clinical outcomes. Our preliminary findings suggest that rs10042486 within 5HTR1A promoter region could be associated with SCZ and with clinical improvement on PANSS total, positive and negative scores in Korean patients with SCZ. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 313 | Behav. Brain Res. 2012 Jan 226: 218-23 |
| PMID | 21944941 |
| Title | Cognition in female transmembrane domain neuregulin 1 mutant mice. |
| Abstract | Neuregulin 1 (NRG1) has been implicated in the development of schizophrenia and influences key neurodevelopmental processes such as myelination and neuronal migration. The heterozygous transmembrane domain NRG1 mutant mouse (NRG1 TM HET) exhibits a sex-specific phenotype relevant for schizophrenia research, which is characterized by the development of locomotor hyperactivity, social withdrawal, and changes to the serotonergic system. Cognitive impairments are characteristic of schizophrenia patients and male NRG1 TM HET mice exhibit cognitive deficits in novel object recognition and contextual fear conditioning. Thus, we investigated the cognitive performance of female NRG1 mutants, using a cognitive test battery for a variety of paradigms, including fear conditioning, cheeseboard, Y maze, object exploration and passive avoidance. Female NRG1 mutant mice displayed impairments in the fear conditioning tasks, including significantly reduced fear conditioning to a context and a strong trend towards a decreased ability for cue fear conditioning. These cognitive deficits were task-specific, as no differences were seen between mutant and control mice in spatial learning of the cheeseboard for reference memory measures, in the Y-maze for working memory measures, or in novel object recognition and passive avoidance paradigms. These findings indicate that neuregulin 1 plays only a minor role in cognition in female test mice. The current study provides a further behavioural validation of this genetic mouse model for the schizophrenia candidate gene neuregulin 1 and confirms the importance of considering female test animals in animal models for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 314 | J. Mol. Neurosci. 2012 Mar 46: 476-82 |
| PMID | 21858616 |
| Title | Lack of associations of neuregulin 1 variations with schizophrenia and smooth pursuit eye movement abnormality in a Korean population. |
| Abstract | schizophrenia is a serious and disabling mental disorder with a high heritability rate. The human neuregulin 1 (NRG1) on 8p12 has been implicated as a candidate gene for schizophrenia. However, controversial results of the associations of NRG1 polymorphisms with schizophrenia and related phenotypes have been reported. In this study, four NRG1 single nucleotide polymorphisms, three in the promoter region, and one nonsynonymous in coding region, were genotyped in a total of 825 subject including 435 schizophrenia cases and 390 normal controls of Korean ethnicity. Although logistic association analysis of NRG1 polymorphisms and haplotypes with schizophrenia showed a nominal association in rs4623364G?>?C (P?=?0.04), the significance disappeared after corrections for multiple testing (corrected P?>?0.05). Additional case/control and multiple regression analyses in schizophrenia patients using a method that measures the smooth pursuit eye movement (SPEM) function globally based on natural logarithmic values of the signal/noise ratio also showed no association between NRG1 variants and SPEM abnormality among patients with schizophrenia (P?>?0.05). Despite the need for further replications in other cohorts, our findings provide additional supporting information that four variants in NRG1 investigated in this study may not be associated with schizophrenia and its related SPEM function in a Korean population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 315 | Neuropharmacology 2012 Mar 62: 1204-20 |
| PMID | 21557953 |
| Title | Mouse models of genetic effects on cognition: relevance to schizophrenia. |
| Abstract | Cognitive dysfunction is a core feature of schizophrenia. Growing evidence indicates that a wide variety of genetic mutations and polymorphisms impact cognition and may thus be implicated in various aspects of this mental disorder. Despite differences between human and rodent brain structure and function, genetic mouse models have contributed critical information about brain mechanisms involved in cognitive processes. Here, we summarize discoveries of genetic modifications in mice that impact cognition. Based on functional hypotheses, gene modifications within five model systems are described: 1) dopamine (D1, D2, D3, D4, D5, DAT, COMT, MAO); 2) glutamate (GluR-A, NR1, NR2A, NR2B, GRM2, GRM3, GLAST); 3) GABA (?(5), ?(2), ?(4), ?GABA(A), GABA(B(1)), GAT1); 4) acetylcholine (nAChR?2, ?7, CHRM1); and 5) calcium (CaMKII-?, neurogranin, CaMKK?, CaMKIV). We also consider other risk-associated genes for schizophrenia such as dysbindin (DTNBP1), neuregulin (NRG1), disrupted-in-schizophrenia1 (DISC1), reelin and proline dehydrogenase (PRODH). Because of the presumed importance of environmental factors, we further consider genetic modifications within the stress-sensitive systems of corticotropin-releasing factor (CRF), brain-derived neurotrophic factor (BDNF) and the endocannabinoid systems. We highlight the missing information and limitations of cognitive assays in genetically modified mice models relevant to schizophrenia pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 316 | Scientifica (Cairo) 2012 -1 2012: 560514 |
| PMID | 24278715 |
| Title | The Association between COMT, BDNF, and NRG1 and Premorbid Social Functioning in Patients with Psychosis, Their Relatives, and Controls. |
| Abstract | We investigated the influences of putative candidate genes for psychosis on premorbid social adjustment and on premorbid schizoid-schizotypal traits. A family-based sample was used including 177 patients with schizophrenia or bipolar I disorder with a history of psychotic symptoms, 86 of their unaffected relatives, and 116 unrelated healthy controls. Association analyses on the combined sample were conducted using the Statistical Analysis for Genetic Epidemiology software (SAGE) and adjusting for age, sex, clinical group, and the family-based nature of the data. The COMT Val(158)Met and BDNF Val(66)Met polymorphisms showed no evidence of association with either phenotype. The SNP rs221533 of the NRG1 gene was significantly associated with premorbid adjustment in adolescence with TT homozygous subjects having a poorer performance than C allele carriers. In the context of neurodevelopmental disorders such as schizophrenia and other psychoses, this finding is plausible; however, it is preliminary and requires replication in an independent sample. In a broader sense, the use of intermediate quantitative phenotypes such as the ones presented in this study may be of help to understand the mechanism of action of genetic risk factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 317 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jun 159B: 422-8 |
| PMID | 22467496 |
| Title | Association study of neuregulin 1 gene polymorphisms with auditory P300 in schizophrenia. |
| Abstract | Neuregulin 1 (NRG1), a gene involved with myelin production has been shown to have a positive correlation with schizophrenia. Event-related potentials (ERPs) studies provide the evidence of disturbed electrophysiologic marker in schizophrenia. The present study investigated the association of NRG1 genotypes with P300 in schizophrenia. Three polymorphisms in NRG1 gene were detected in 287 Chinese Han schizophrenics and 120 healthy control subjects. Among the total sample, 140 patients and 96 controls underwent P300. There were no significant differences for genotype distributions and allele frequencies between schizophrenic group and the control. A significant difference was observed between the schizophrenic patients and controls in the AT haplotype, with Odds Ratio 0.304 (P = 0.000882, 95% CI = 0.145-0.636). P300 amplitude in the schizophrenic group was significantly lower than that of the controls at Fz, Cz, Pz. P300 latency in the schizophrenic group was also significantly longer than that of the controls at Cz, Pz, Fz. Significant differences of P300 latency between three genotypes of rs3924999 were found at Cz and Pz both in schizophrenic group and the controls. The G/G carriers of rs3924999 tended to perform worse in the P300 latency as compared to A/A or A/G carriers both in the schizophrenia and controls. There were no significant differences for P300 latency and amplitude between schizophrenic group and controls for AT haplotype. NRG1 gene is a susceptible gene for Chinese Han schizophrenia and AT haplotype might have the protective role in the schizophrenia. Rs3924999 in NRG1 gene might functionally impact cognitive processing. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 318 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jun 159B: 422-8 |
| PMID | 22467496 |
| Title | Association study of neuregulin 1 gene polymorphisms with auditory P300 in schizophrenia. |
| Abstract | Neuregulin 1 (NRG1), a gene involved with myelin production has been shown to have a positive correlation with schizophrenia. Event-related potentials (ERPs) studies provide the evidence of disturbed electrophysiologic marker in schizophrenia. The present study investigated the association of NRG1 genotypes with P300 in schizophrenia. Three polymorphisms in NRG1 gene were detected in 287 Chinese Han schizophrenics and 120 healthy control subjects. Among the total sample, 140 patients and 96 controls underwent P300. There were no significant differences for genotype distributions and allele frequencies between schizophrenic group and the control. A significant difference was observed between the schizophrenic patients and controls in the AT haplotype, with Odds Ratio 0.304 (P = 0.000882, 95% CI = 0.145-0.636). P300 amplitude in the schizophrenic group was significantly lower than that of the controls at Fz, Cz, Pz. P300 latency in the schizophrenic group was also significantly longer than that of the controls at Cz, Pz, Fz. Significant differences of P300 latency between three genotypes of rs3924999 were found at Cz and Pz both in schizophrenic group and the controls. The G/G carriers of rs3924999 tended to perform worse in the P300 latency as compared to A/A or A/G carriers both in the schizophrenia and controls. There were no significant differences for P300 latency and amplitude between schizophrenic group and controls for AT haplotype. NRG1 gene is a susceptible gene for Chinese Han schizophrenia and AT haplotype might have the protective role in the schizophrenia. Rs3924999 in NRG1 gene might functionally impact cognitive processing. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 319 | Schizophr. Res. 2013 Oct 150: 262-5 |
| PMID | 23899995 |
| Title | Hypomethylation of neuregulin in rats selectively bred for reduced sensorimotor gating. |
| Abstract | Low prepulse inhibition (PPI) of startle is associated with reduced sensorimotor gating found in schizophrenia. In rats with breeding-induced low PPI neuregulin (NRG1) methylation was significantly decreased in brain regions associated with this phenotype and with schizophrenia, i.e., the medial prefrontal cortex, the nucleus accumbens, and the ventral hippocampus, while methylation in the amygdala and dorsal hippocampus was less affected. The dopamine D2 receptor (DRD2) promoter region showed negligible changes between groups. Rats with low PPI may be used to understand the reduced epigenetic regulation found in schizophrenia, and eventually lead to the development of novel therapies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 320 | J. Neurosci. 2013 Dec 33: 19295-303 |
| PMID | 24305825 |
| Title | Regulation of spine formation by ErbB4 in PV-positive interneurons. |
| Abstract | The trophic factor neuregulin 1 (NRG1) and its receptor ErbB4 are schizophrenia candidate genes. NRG1-ErbB4 signaling was thought to regulate spine formation and function in a cell-autonomous manner. Yet, recent studies indicate that ErbB4 expression is largely restricted to GABAergic interneurons and is very low or absent in pyramidal cells. Here, we generated and characterized cell type-specific ErbB4 mutant and transgenic mice. Spine density and the number of excitatory synapses were unaltered by neither deletion nor overexpression of ErbB4 in pyramidal neurons. However, spine density and excitatory synapse number were reduced in PV-ErbB4(-/-) mice where ErbB4 was selectively ablated in parvalbumin-positive GABAergic interneurons. Concurrently, basal glutamate transmission was impaired in PV-ErbB4(-/-) mice, but not in mice where ErbB4 was deleted or overexpressed in pyramidal neurons. Our results demonstrate a role of ErbB4 in PV-positive interneurons for spine formation in excitatory neurons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 321 | J. Neurochem. 2013 Sep 126: 625-35 |
| PMID | 23742124 |
| Title | Neuregulin1 signaling promotes dendritic spine growth through kalirin. |
| Abstract | The biological functions of the neuregulin 1 (NRG1) and ERBB4 genes have received much recent attention due to several studies showing associations between these genes and schizophrenia. Moreover, reduced forebrain dendritic spine density is a consistent feature of schizophrenia. It is thus important to understand the mechanisms whereby NRG1 and erbB4 modulate spine morphogenesis. Here, we show that long-term incubation with NRG1 increases both spine size and density in cortical pyramidal neurons. NRG1 also enhances the content of ?-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors in spines. Knockdown of ERBB4 expression prevented the effects of NRG1 on spine size, but not on spine density. The effects of NRG1 and erbB4 on spines were mediated by the RacGEF kalirin, a well-characterized regulator of dendritic spines. Finally, we show that environmental enrichment, known to promote spine growth, robustly enhances the levels of erbB4 protein in the forebrain. These findings provide a mechanistic link between NRG1 signaling and spine morphogenesis |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 322 | Am. J. Med. Genet. A 2013 Jun 161A: 1487-90 |
| PMID | 23633123 |
| Title | A new single gene deletion on 2q34: ERBB4 is associated with intellectual disability. |
| Abstract | We report on a 15-year-old patient with hyperactivity, intellectual disability and severe speech developmental delay. An array CGH analysis revealed de novo 2q34 deletion, 958?kb in size, involving a single protein coding gene ERBB4 (position 212,505,294-213,463,152; NCBI build 36). The ERBB4 gene is important in numerous neurobiological processes in both the developing and the adult brain. The NRG1-ERBB4 signaling pathway has been recently implicated in the pathophysiology of schizophrenia and epilepsy. Many risk haplotypes were identified in several studies across different populations. The severe clinical consequences in our patient demonstrate that the haploinsufficiency of ERBB4 is crucial for intellectual and cognitive function. These observations are compatible with previously reported results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 323 | Genome 2013 Oct 56: 619-25 |
| PMID | 24237343 |
| Title | Neuregulin 1-alpha regulates phosphorylation, acetylation, and alternative splicing in lymphoblastoid cells. |
| Abstract | Neuregulins (NRGs) are signaling molecules involved in various cellular and developmental processes. Abnormal expression and (or) genomic variations of some of these molecules, such as NRG1, have been associated with disease conditions such as cancer and schizophrenia. To gain a comprehensive molecular insight into possible pathways/networks regulated by NRG1-alpha, we performed a global expression profiling analysis on lymphoblastoid cell lines exposed to NRG1-alpha. Our data show that this signaling molecule mainly regulates coordinated expression of genes involved in three processes: phosphorylation, acetylation, and alternative splicing. These processes have fundamental roles in proper development and function of various tissues including the central nervous system (CNS)--a fact that may explain conditions associated with NRG1 dysregulations such as schizophrenia. The data also suggest NRG1-alpha regulates genes (FBXO41) and miRNAs (miR-33) involved in cholesterol metabolism. Moreover, RPN2, a gene already shown to be dysregulated in breast cancer cells, is also differentially regulated by NRG1-alpha treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 324 | Pharmacopsychiatry 2013 Nov 46: 286-91 |
| PMID | 24105081 |
| Title | Female neuregulin 1 heterozygous mice require repeated exposure to ??-tetrahydrocannabinol to alter sensorimotor gating function. |
| Abstract | The schizophrenia susceptibility gene neuregulin 1 (NRG1) confers vulnerability to the neurobehavioural eff ects of cannabinoids differently across sexes. Male but not female NRG1 heterozygous (HET) mice display facilitation of prepulse inhibition (PPI) to acute ??-tetrahydrocannabinol (THC) exposure compared to WT controls. We aim to observe whether repeated administration of THC may overcome the acute insensitivity of female NRG1 HET mice to THC exposure. Female NRG1 HET mice and WT controls were administered THC daily for 21 days, with PPI and anxiety-related behaviour in the light-dark test (LD) examined on the fi rst and last day of treatment and 21 days after cessation of dosing. Following repeated, but not acute THC exposure, female NRG1 HET mice displayed THC-induced facilitation of PPI which was not observed in WT mice treated with THC. There were no residual eff ects of THC on PPI in either genotype when assessed 21 days following the final THC dose. An anxiogenic response to THC was evident following repeated, but not acute, administration in the LD test in both genotypes. These findings show that the acute insensitivity of female NRG1 HET mice to THC-induced PPI facilitation may be overcome following repeated THC exposure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 325 | Front Behav Neurosci 2013 -1 7: 106 |
| PMID | 23966917 |
| Title | Neuregulin 1: a prime candidate for research into gene-environment interactions in schizophrenia? Insights from genetic rodent models. |
| Abstract | schizophrenia is a multi-factorial disease characterized by a high heritability and environmental risk factors. In recent years, an increasing number of researchers worldwide have started investigating the "two-hit hypothesis" of schizophrenia predicting that genetic and environmental risk factors (GxE) interactively cause the development of the disorder. This work is starting to produce valuable new animal models and reveal novel insights into the pathophysiology of schizophrenia. This mini review will focus on recent advancements in the field made by challenging mutant and transgenic rodent models for the schizophrenia candidate gene neuregulin 1 (NRG1) with particular environmental factors. It will outline results obtained from mouse and rat models for various NRG1 isoforms/isoform types (e.g., transmembrane domain NRG1, Type II NRG1), which have been exposed to different forms of stress (acute versus chronic, restraint versus social) and housing conditions (standard laboratory versus minimally enriched housing). These studies suggest NRG1 as a prime candidate for GxE interactions in schizophrenia rodent models and that the use of rodent models will enable a better understanding of GxE interactions and the underlying mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 326 | Neuron 2013 May 78: 644-57 |
| PMID | 23719163 |
| Title | Reversal of behavioral deficits and synaptic dysfunction in mice overexpressing neuregulin 1. |
| Abstract | Neuregulin 1 (NRG1) is a susceptibility gene of schizophrenia, a disabling mental illness that affects 1% of the general population. Here, we show that ctoNRG1 mice, which mimic high levels of NRG1 observed in forebrain regions of schizophrenic patients, exhibit behavioral deficits and hypofunction of glutamatergic and GABAergic pathways. Intriguingly, these deficits were diminished when NRG1 expression returned to normal in adult mice, suggesting that damage which occurred during development is recoverable. Conversely, increase of NRG1 in adulthood was sufficient to cause glutamatergic impairment and behavioral deficits. We found that the glutamatergic impairment by NRG1 overexpression required LIM domain kinase 1 (LIMK1), which was activated in mutant mice, identifying a pathological mechanism. These observations demonstrate that synaptic dysfunction and behavioral deficits in ctoNRG1 mice require continuous NRG1 abnormality in adulthood, suggesting that relevant schizophrenia may benefit from therapeutic intervention to restore NRG1 signaling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 327 | Front Cell Neurosci 2013 -1 7: 18 |
| PMID | 23447438 |
| Title | What does a mouse tell us about neuregulin 1-cannabis interactions? |
| Abstract | The link between cannabis and psychosis has been debated although there is substantial epidemiological evidence showing that cannabis increases the risk of psychosis. It has been hypothesized that schizophrenia patients carrying particular risk genes might be more sensitive to the psychosis-inducing effects of cannabis than other patients and healthy test subjects. Here we review the effects of cannabinoids on a mutant mouse model for the schizophrenia candidate gene neuregulin 1 (NRG1). The studies suggest a complex interaction between cannabis and NRG1: the neuro-behavioral effects of cannabinoids were different in NRG1 mutant and control mice and depended on exposure time, sex, and age of test animals. This research provides the first evidence of complex cannabis-NRG1 interactions suggesting NRG1 as a prime target for future clinical investigations. Furthermore, it highlights that animal model research can broaden our understanding of the complex multi-factorial etiology of schizophrenia. Finally, the findings are important to preventive psychiatry: if the genes that confer genetic vulnerability to cannabis-induced psychosis were identified patients at-high risk could be forewarned of the potential dangers of cannabis abuse. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 328 | Expert Rev Neurother 2013 Jan 13: 37-47 |
| PMID | 23253390 |
| Title | Progress in imaging the effects of psychosis susceptibility gene variants. |
| Abstract | Genetic imaging has become an increasingly popular tool that utilizes neuroimaging techniques to investigate the impact of genetic variation on the structure, function and connectivity of the brain. Combining genetic and neuroimaging domains is a promising approach to further the understanding of the neural mechanisms involved in mediating the effect of genetic variants on psychosis risk, with the potential to explore individual vulnerability to psychiatric illness. Imaging genetics approaches have successfully been applied to a wide range of risk genes for schizophrenia. This article reviews the recent literature on genetic imaging in schizophrenia, using two key susceptibility genes for psychosis, DISC1 and NRG1, as examples. The authors explore challenges and future perspectives in the field, including the need for future research to focus on epistatic effects of multiple common variants, account for the complexity of gene-environment interactions, characterize rare high-risk structural variants and identify more effective neuroimaging paradigms that reach a higher threshold of heritability. Ultimately, this review highlights that genetic imaging remains a research technique, and further progress and integration with other techniques will be required before we can predict the onset and development of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 329 | Neuropsychiatr Dis Treat 2013 -1 9: 1573-82 |
| PMID | 24143106 |
| Title | Evidence for single nucleotide polymorphisms and their association with bipolar disorder. |
| Abstract | Bipolar disorder (BD) is a complex disorder with a number of susceptibility genes and environmental risk factors involved in its pathogenesis. In recent years, huge progress has been made in molecular techniques for genetic studies, which have enabled identification of numerous genomic regions and genetic variants implicated in BD across populations. Despite the abundance of genetic findings, the results have often been inconsistent and not replicated for many candidate genes/single nucleotide polymorphisms (SNPs). Therefore, the aim of the review presented here is to summarize the most important data reported so far in candidate gene and genome-wide association studies. Taking into account the abundance of association data, this review focuses on the most extensively studied genes and polymorphisms reported so far for BD to present the most promising genomic regions/SNPs involved in BD. The review of association data reveals evidence for several genes (SLC6A4/5-HTT [serotonin transporter gene], BDNF [brain-derived neurotrophic factor], DAOA [D-amino acid oxidase activator], DTNBP1 [dysbindin], NRG1 [neuregulin 1], DISC1 [disrupted in schizophrenia 1]) to be crucial candidates in BD, whereas numerous genome-wide association studies conducted in BD indicate polymorphisms in two genes (CACNA1C [calcium channel, voltage-dependent, L type, alpha 1C subunit], ANK3 [ankyrin 3]) replicated for association with BD in most of these studies. Nevertheless, further studies focusing on interactions between multiple candidate genes/SNPs, as well as systems biology and pathway analyses are necessary to integrate and improve the way we analyze the currently available association data. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 330 | Schizophr Bull 2013 May 39: 518-26 |
| PMID | 22499782 |
| Title | Brain vs behavior: an effect size comparison of neuroimaging and cognitive studies of genetic risk for schizophrenia. |
| Abstract | Genetic variants associated with increased risk for schizophrenia (SZ) are hypothesized to be more penetrant at the level of brain structure and function than at the level of behavior. However, to date the relative sensitivity of imaging vs cognitive measures of these variants has not been quantified. We considered effect sizes associated with cognitive and imaging studies of 9 robust SZ risk genes (DAOA, DISC1, DTNBP1, NRG1, RGS4, NRGN, CACNA1C, TCF4, and ZNF804A) published between January 2005-November 2011. Summary data was used to calculate estimates of effect size for each significant finding. The mean effect size for each study was categorized as small, medium, or large and the relative frequency of each category was compared between modalities and across genes. Random effects meta-analysis was used to consider the impact of experimental methodology on effect size. Imaging studies reported mostly medium or large effects, whereas cognitive investigations commonly reported small effects. Meta-analysis confirmed that imaging studies were associated with larger effects. Effect size estimates were negatively correlated with sample size but did not differ as a function of gene nor imaging modality. These observations support the notion that SZ risk variants show larger effects, and hence greater penetrance, when characterized using indices of brain structure and function than when indexed by cognitive measures. However, it remains to be established whether this holds true for individual risk variants, imaging modalities, or cognitive functions, and how such effects may be mediated by a relationship with sample size and other aspects of experimental variability. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 331 | Behav. Brain Res. 2013 Nov 257: 118-28 |
| PMID | 24076151 |
| Title | Forebrain gene expression predicts deficits in sensorimotor gating after isolation rearing in male rats. |
| Abstract | Compared to socially housed (SH) rats, adult isolation-reared (IR) rats exhibit phenotypes relevant to schizophrenia (SZ), including reduced prepulse inhibition (PPI) of startle. PPI is normally regulated by the medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). We assessed PPI, auditory-evoked local field potentials (LFPs) and expression of seven PPI- and SZ-related genes in the mPFC and NAC, in IR and SH rats. Buffalo (BUF) rats were raised in same-sex groups of 2-3 (SH) or in isolation (IR). PPI was measured early (d53) and later in adulthood (d74); LFPs were measured approximately on d66. Brains were processed for RT-PCR measures of mPFC and NAC expression of Comt, Erbb4, Grid2, Ncam1, Slc1a2, NRG1 and Reln. Male IR rats exhibited PPI deficits, most pronounced at d53; male and female IR rats had significantly elevated startle magnitude on both test days. Gene expression levels were not significantly altered by IR. PPI levels (d53) were positively correlated with mPFC expression of several genes, and negatively correlated with NAC expression of several genes, in male IR but not SH rats. Late (P90) LFP amplitudes correlated significantly with expression levels of 6/7 mPFC genes in male rats, independent of rearing. After IR that disrupts early adult PPI in male BUF rats, expression levels of PPI- and SZ-associated genes in the mPFC correlate positively with PPI, and levels in the NAC correlate negatively with PPI. These results support the model that specific gene-behavior relationships moderate the impact of early-life experience on SZ-linked behavioral and neurophysiological markers. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 332 | Neuropharmacology 2013 Dec 75: 38-46 |
| PMID | 23810830 |
| Title | Coupling of gene expression in medial prefrontal cortex and nucleus accumbens after neonatal ventral hippocampal lesions accompanies deficits in sensorimotor gating and auditory processing in rats. |
| Abstract | After neonatal ventral hippocampal lesions (NVHLs), adult rats exhibit evidence of neural processing deficits relevant to schizophrenia, including reduced prepulse inhibition (PPI) of acoustic startle and impaired sensory processing. In intact rats, the regulation of PPI by the ventral hippocampus (VH) is mediated via interactions with medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). We assessed PPI, auditory-evoked responses and expression of 7 schizophrenia-related genes in mPFC and NAC, in adult rats after sham- or real NVHLs. Male inbred Buffalo (BUF) rat pups (d7; n=36) received either vehicle or ibotenic acid infusion into the VH. PPI and auditory-evoked dentate gyrus local field potentials (LFPs) were measured on d56 and d66, respectively. Brains were processed for RT-PCR measures of mPFC and NAC Comt, Erbb4, Grid2, Ncam1, Slc1a2, NRG1 and Reln. NVHL rats exhibited significant deficits in PPI (p=0.005) and LFPs (p<0.015) proportional to lesion size. Sham vs. NVHL rats did not differ in gene expression levels in mPFC or NAC. As we previously reported, multiple gene expression levels were highly correlated within- (mean r's?0.5), but not across-brain regions (mean r's?0). However, for three genes--Comt, Slc1a2 and Ncam1--after NVHLs, expression levels became significantly correlated, or "coupled," across the mPFC and NAC (p's<0.03, 0.002 and 0.05, respectively), and the degree of "coupling" increased with VH lesion size. After NVHLs that disrupt PPI and auditory processing, specific gene expression levels suggest an abnormal functional coupling of the mPFC and NAC. This model of VH-mPFC-NAC network dysfunction after NVHLs may have implications for understanding the neural basis for PPI- and related sensory processing deficits in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 333 | Neuroscience 2013 Sep 249: 31-42 |
| PMID | 23022220 |
| Title | The interaction of disrupted type II neuregulin 1 and chronic adolescent stress on adult anxiety- and fear-related behaviors. |
| Abstract | The incidence of anxiety, mood, substance abuse disorders and schizophrenia increases during adolescence. Epidemiological evidence confirms that exposure to stress during sensitive periods of development can create vulnerabilities that put genetically predisposed individuals at increased risk for psychiatric disorders. Neuregulin 1 (NRG1) is a frequently identified schizophrenia susceptibility gene that has also been associated with the psychotic features of bipolar disorder. Previously, we established that Type II NRG1 is expressed in the hypothalamic-pituitary-adrenal (HPA) axis neurocircuitry. We also found, using a line of NRG1 hypomorphic rats (NRG1(Tn)), that genetic disruption of Type II NRG1 results in altered HPA axis function and environmental reactivity. The present studies used the NRG1(Tn) rats to test whether Type II NRG1 gene disruption and chronic stress exposure during adolescence interact to alter adult anxiety- and fear-related behaviors. Male and female NRG1(Tn) and wild-type rats were exposed to chronic variable stress (CVS) during mid-adolescence and then tested for anxiety-like behavior, cued fear conditioning and basal corticosterone secretion in adulthood. The disruption of Type II NRG1 alone significantly impacts rat anxiety-related behavior by reversing normal sex-related differences and impairs the ability to acquire cued fear conditioning. Sex-specific interactions between genotype and adolescent stress also were identified such that CVS-treated wild-type females exhibited a slight reduction in anxiety-like behavior and basal corticosterone, while CVS-treated NRG1(Tn) females exhibited a significant increase in cued fear extinction. These studies confirm the importance of Type II NRG1 in anxiety and fear behaviors and point to adolescence as a time when stressful experiences can shape adult behavior and HPA axis function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 334 | PLoS ONE 2013 -1 8: e60099 |
| PMID | 23555897 |
| Title | The DAO gene is associated with schizophrenia and interacts with other genes in the Taiwan Han Chinese population. |
| Abstract | schizophrenia is a highly heritable disease with a polygenic mode of inheritance. Many studies have contributed to our understanding of the genetic underpinnings of schizophrenia, but little is known about how interactions among genes affect the risk of schizophrenia. This study aimed to assess the associations and interactions among genes that confer vulnerability to schizophrenia and to examine the moderating effect of neuropsychological impairment. We analyzed 99 SNPs from 10 candidate genes in 1,512 subject samples. The permutation-based single-locus, multi-locus association tests, and a gene-based multifactorial dimension reduction procedure were used to examine genetic associations and interactions to schizophrenia. We found that no single SNP was significantly associated with schizophrenia. However, a risk haplotype, namely A-T-C of the SNP triplet rsDAO7-rsDAO8-rsDAO13 of the DAO gene, was strongly associated with schizophrenia. Interaction analyses identified multiple between-gene and within-gene interactions. Between-gene interactions including DAO*DISC1 , DAO*NRG1 and DAO*RASD2 and a within-gene interaction for CACNG2 were found among schizophrenia subjects with severe sustained attention deficits, suggesting a modifying effect of impaired neuropsychological functioning. Other interactions such as the within-gene interaction of DAO and the between-gene interaction of DAO and PTK2B were consistently identified regardless of stratification by neuropsychological dysfunction. Importantly, except for the within-gene interaction of CACNG2, all of the identified risk haplotypes and interactions involved SNPs from DAO. These results suggest that DAO, which is involved in the N-methyl-d-aspartate receptor regulation, signaling and glutamate metabolism, is the master gene of the genetic associations and interactions underlying schizophrenia. Besides, the interaction between DAO and RASD2 has provided an insight in integrating the glutamate and dopamine hypotheses of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 335 | Neuroscience 2013 Sep 248: 670-80 |
| PMID | 23811072 |
| Title | A neuregulin 1 transmembrane domain mutation causes imbalanced glutamatergic and dopaminergic receptor expression in mice. |
| Abstract | The neuregulin 1 gene has repeatedly been identified as a susceptibility gene for schizophrenia, thus mice with genetic mutations in this gene offer a valuable tool for studying the role of neuregulin 1 in schizophrenia-related neurotransmission. In this study, slide-based receptor autoradiography was used to quantify glutamatergic N-methyl-d-aspartate (NMDA), dopaminergic D2, cannabinoid CB1 and acetylcholine M1/4 receptor levels in the brains of male heterozygous transmembrane domain neuregulin 1 mutant (NRG1(+/-)) mice at two ages. Mutant mice expressed small but significant increases in NMDA receptor levels in the cingulate cortex (7%, p=0.044), sensory cortex (8%, p=0.024), and motor cortex (8%, p=0.047), effects that were independent of age. In the nucleus accumbens and thalamus NRG1(+/-) mice exhibited age-dependent alterations in NMDA receptors. NRG1(+/-) mice showed a statistically significant increase in NMDA receptor levels in the nucleus accumbens of 14-week-old NRG1(+/-) mice compared to control littermates of the same age (12%, p=0.026), an effect that was not seen in 20-week-old mice. In contrast, NMDA receptor levels in the thalamus, while initially unchanged in 14-week-old mice, were then decreased in the 20-week-old NRG1(+/-) mice compared to control littermates of the same age (14%, p=0.011). NRG1(+/-) mutant mice expressed a significant reduction in D2 receptor levels (13-16%) in the striatum compared to controls, independent of age. While there was a borderline significant increase (6%, p=0.058) in cannabinoid CB1 receptor levels in the substantia nigra of NRG1(+/-) mice compared to controls, CB1 as well as acetylcholine M1/4 receptors showed no change in NRG1(+/-) mice in any other brain region examined. These data indicate that a NRG1 transmembrane mutation produces selective imbalances in glutamatergic and dopaminergic neurotransmission, which are two key systems believed to contribute to schizophrenia pathogenesis. While the effects on these systems are subtle, they may underlie the susceptibility of these mutants to further impacts. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 336 | Transl Psychiatry 2013 -1 3: e264 |
| PMID | 23715299 |
| Title | Multiple variants aggregate in the neuregulin signaling pathway in a subset of schizophrenia patients. |
| Abstract | Despite the strongly held view that schizophrenia (SZ) shows substantial genetic heterogeneity, pathway heterogeneity, as seen in cancer where different pathways are affected in similar tumors, has not been explored. We explore this possibility in a case-only study of the neuregulin signaling pathway (NSP), which has been prominently implicated in SZ and for which there is detailed knowledge on the ligand- and receptor-processing steps through ?- and ?-secretase cleavage. We hypothesize that more than one damaging variants in the NSP genes might be necessary to cause disease, leading to an apparent clustering of such variants in only the few patients with affected NSP. We analyze linkage and next-generation sequencing results for the genes encoding components of the pathway, including NRG1, NRG3, ERBB4, ?-secretase and the ?-secretase complex. We find multiple independent examples of supporting evidence for this hypothesis: (i) increased linkage scores over NSP genes, (ii) multiple positive interlocus correlations of linkage scores across families suggesting each family is linked to either many or none of the genes, (iii) aggregation of predicted damaging variants in a subset of individuals and (iv) significant phenotypic differences of the subset of patients carrying such variants. Collectively, our data strongly support the hypothesis that the NSP is affected by multiple damaging variants in a subset of phenotypically distinct patients. On the basis of this, we propose a general model of pathway heterogeneity in SZ, which, in part, may explain its phenotypic variability and genetic complexity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 337 | Am. J. Physiol., Cell Physiol. 2013 Jul 305: C197-206 |
| PMID | 23703525 |
| Title | Neuregulin-1/ErbB4 signaling regulates Kv4.2-mediated transient outward K+ current through the Akt/mTOR pathway. |
| Abstract | Neuregulin-1 (NRG-1) is a member of a family of neurotrophic factors that is required for the differentiation, migration, and development of neurons. NRG-1 signaling is thought to contribute to both neuronal development and the neuropathology of schizophrenia, which is believed to be a neurodevelopmental disorder. However, few studies have investigated the role of NRG-1 on voltage-gated ion channels. In this study, we report that NRG-1 specifically increases the density of transient outward K(+) currents (IA) in rat cerebellar granule neurons (CGNs) in a time-dependent manner without modifying the activation or inactivation properties of IA channels. The increase in IA density is mediated by increased protein expression of Kv4.2, the main ?-subunit of the IA channel, most likely by upregulation of translation. The effect of NRG-1 on IA density and Kv4.2 expression was only significant in immature neurons. Mechanistically, both Akt and mammalian target of rapamycin (mTOR) signaling pathways are required for the increased NRG-1-induced IA density and expression of Kv4.2. Moreover, pharmacological blockade of the ErbB4 receptor reduced the effect of NRG-1 on IA density and Kv4.2 induction. Our data reveal, for the first time, that stimulation of ErbB4 signaling by NRG-1 upregulates the expression of K(+) channel proteins via activation of the Akt/mTOR signaling pathway and plays an important role in neuronal development and maturation. NRG1 does not acutely change IA and delayed-rectifier outward (IK) of rat CGNs, suggesting that it may not alter excitability of immature neurons by altering potassium channel property. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 338 | Pharmacol. Biochem. Behav. 2013 Jul 108: 44-53 |
| PMID | 23603030 |
| Title | Enhanced interaction among ErbB4, PSD-95 and NMDAR by chronic MK-801 treatment is associated with behavioral abnormalities. |
| Abstract | The neuregulin 1 (NRG1)-ErbB4 signaling pathway has been implicated in the pathophysiology of schizophrenia. Recent studies suggest that this pathway may interact with the N-methyl-d-aspartate receptor (NMDAR) via the postsynaptic scaffold protein PSD-95. This interaction is of particular interest given the leading role of the NMDAR hypofunction in schizophrenia. The present study investigated the short- and long-term effects of chronic NMDAR blockade on the functional interaction between the two systems in rat prefrontal cortex and hippocampus using immunoprecipitation. Adult male Wistar rats were treated intraperitoneally with MK-801 (0.25 mg/kg) or saline for 28 days. Twenty-four hours after the last injection, the associations of ErbB4 with PSD-95 and NMDAR were enhanced in the prefrontal cortex, whereas only phosphorylated-ErbB4 relative to ErbB4 was increased in the hippocampus. These effects, however, were not detectable 12 days after the last MK-801 treatment, indicating the reversible nature of these changes. We also investigated the effects of chronic MK-801 treatment on locomotion, prepulse inhibition, recognition memory, and spatial working memory. The results showed that this treatment led to decreased locomotor activity, reduced exploration in the center arena, and elevated startle magnitudes, indicating an anxiety-like phenotype. Taken together, our findings suggest that the NRG1-ErbB4 signaling could be modulated by repeated NMDAR blockade, and provide further evidence for the cross-talk between the two signaling pathways. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 339 | Psychopharmacology (Berl.) 2013 Mar 226: 201-15 |
| PMID | 23389757 |
| Title | Neuregulin-1 signalling and antipsychotic treatment: potential therapeutic targets in a schizophrenia candidate signalling pathway. |
| Abstract | Identifying the signalling pathways underlying the pathophysiology of schizophrenia is an essential step in the rational development of new antipsychotic drugs for this devastating disease. Evidence from genetic, transgenic and post-mortem studies have strongly supported neuregulin-1 (NRG1)-ErbB4 signalling as a schizophrenia susceptibility pathway. NRG1-ErbB4 signalling plays crucial roles in regulating neurodevelopment and neurotransmission, with implications for the pathophysiology of schizophrenia. Post-mortem studies have demonstrated altered NRG1-ErbB4 signalling in the brain of schizophrenia patients. Antipsychotic drugs have different effects on NRG1-ErbB4 signalling depending on treatment duration. Abnormal behaviours relevant to certain features of schizophrenia are displayed in NRG1/ErbB4 knockout mice or those with NRG1/ErbB4 over-expression, some of these abnormalities can be improved by antipsychotic treatment. NRG1-ErbB4 signalling has extensive interactions with the GABAergic, glutamatergic and dopaminergic neurotransmission systems that are involved in the pathophysiology of schizophrenia. These interactions provide a number of targets for the development of new antipsychotic drugs. Furthermore, the key interaction points between NRG1-ErbB4 signalling and other schizophrenia susceptibility genes may also potentially provide specific targets for new antipsychotic drugs. In general, identification of these targets in NRG1-ErbB4 signalling and interacting pathways will provide unique opportunities for the development of new generation antipsychotics with specific efficacy and fewer side effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 340 | PLoS ONE 2013 -1 8: e53042 |
| PMID | 23301017 |
| Title | Discovery, validation and characterization of Erbb4 and Nrg1 haplotypes using data from three genome-wide association studies of schizophrenia. |
| Abstract | schizophrenia is one of the most common and complex neuropsychiatric disorders, which is contributed both by genetic and environmental exposures. Recently, it is shown that NRG1-mediated ErbB4 signalling regulates many important cellular and molecular processes such as cellular growth, differentiation and death, particularly in myelin-producing cells, glia and neurons. Recent association studies have revealed genomic regions of NRG1 and ERBB4, which are significantly associated with risk of developing schizophrenia; however, inconsistencies exist in terms of validation of findings between distinct populations. In this study, we aim to validate the previously identified regions and to discover novel haplotypes of NRG1 and ERBB4 using logistic regression models and Haploview analyses in three independent datasets from GWAS conducted on European subjects, namely, CATIE, GAIN and nonGAIN. We identified a significant 6-kb block in ERBB4 between chromosome locations 212,156,823 and 212,162,848 in CATIE and GAIN datasets (p = 0.0206 and 0.0095, respectively). In NRG1, a significant 25-kb block, between 32,291,552 and 32,317,192, was associated with risk of schizophrenia in all CATIE, GAIN, and nonGAIN datasets (p = 0.0005, 0.0589, and 0.0143, respectively). Fine mapping and FastSNP analysis of genetic variation located within significantly associated regions proved the presence of binding sites for several transcription factors such as SRY, SOX5, CEPB, and ETS1. In this study, we have discovered and validated haplotypes of ERBB4 and NRG1 in three independent European populations. These findings suggest that these haplotypes play an important role in the development of schizophrenia by affecting transcription factor binding affinity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 341 | J. Neurosci. 2013 Jun 33: 9655-66 |
| PMID | 23739962 |
| Title | Type III neuregulin 1 is required for multiple forms of excitatory synaptic plasticity of mouse cortico-amygdala circuits. |
| Abstract | The amygdala plays an important role in the formation and storage of memories associated with emotional events. The cortical glutamatergic inputs onto pyramidal neurons in the basolateral nucleus of the amygdala (BLA) contribute to this process. As the interaction between neuregulin 1 (NRG1) and its ErbB receptors has been implicated in the pathological mechanisms of schizophrenia, loss of NRG1 may disrupt cortical-amygdala neural circuits, resulting in altered processing of salient memories. Here we show that NRG1 is critical in multiple forms of plasticity of cortical projections to pyramidal neurons of the BLA. The miniature EPSCs in NRG1 heterozygous animals have a faster time constant of decay and evoked synaptic currents have a smaller NMDA/AMPA ratio than those recorded in wild-type (WT) littermates. Both high-frequency electrical stimulation of cortical inputs and ? burst stimulation combined with nicotine exposure results in long-lasting potentiation in WT animals. However, the same manipulations have little to no effect on glutamatergic synaptic plasticity in the BLA from NRG1 heterozygous mice. Comparison of WT, NRG1 heterozygous animals and ?7 nicotinic receptor heterozygous mice reveals that the sustained phase of potentiation of glutamatergic transmission after ? burst stimulation with or without nicotine only occurs in the WT mice. Together, these findings support the idea that type III NRG1 is essential to multiple aspects of the modulation of excitatory plasticity at cortical-BLA synapses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 342 | J. Pharmacol. Sci. 2013 -1 121: 185-91 |
| PMID | 23449491 |
| Title | Behavioral phenotypes in schizophrenic animal models with multiple combinations of genetic and environmental factors. |
| Abstract | schizophrenia is a multifactorial psychiatric disorder in which both genetic and environmental factors play a role. Genetic [e.g., Disrupted-in-schizophrenia 1 (DISC1), Neuregulin-1 (NRG1)] and environmental factors (e.g., maternal viral infection, obstetric complications, social stress) may act during the developmental period to increase the incidence of schizophrenia. In animal models, interactions between susceptibility genes and the environment can be controlled in ways not possible in humans; therefore, such models are useful for investigating interactions between or within factors in the pathogenesis and pathophysiology of schizophrenia. We provide an overview of schizophrenic animal models investigating interactions between or within factors. First, we reviewed gene-environment interaction animal models, in which schizophrenic candidate gene mutant mice were subjected to perinatal immune activation or adolescent stress. Next, environment-environment interaction animal models, in which mice were subjected to a combination of perinatal immune activation and adolescent administration of drugs, were described. These animal models showed interaction between or within factors; behavioral changes, which were obscured by each factor, were marked by interaction of factors and vice versa. Appropriate behavioral approaches with such models will be invaluable for translational research on novel compounds, and also for providing insight into the pathogenesis and pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 343 | Front Cell Neurosci 2013 -1 7: 15 |
| PMID | 23447498 |
| Title | Novel molecular changes induced by Nrg1 hypomorphism and Nrg1-cannabinoid interaction in adolescence: a hippocampal proteomic study in mice. |
| Abstract | Neuregulin 1 (NRG1) is linked to an increased risk of developing schizophrenia and cannabis dependence. Mice that are hypomorphic for NRG1 (NRG1 HET mice) display schizophrenia-relevant behavioral phenotypes and aberrant expression of serotonin and glutamate receptors. NRG1 HET mice also display idiosyncratic responses to the main psychoactive constituent of cannabis, ?(9)-tetrahydrocannabinol (THC). To gain traction on the molecular pathways disrupted by NRG1 hypomorphism and NRG1-cannabinoid interactions we conducted a proteomic study. Adolescent wildtype (WT) and NRG1 HET mice were exposed to repeated injections of vehicle or THC and their hippocampi were submitted to 2D gel proteomics. Comparison of WT and NRG1 HET mice identified proteins linked to molecular changes in schizophrenia that have not been previously associated with NRG1. These proteins are involved in vesicular release of neurotransmitters such as SNARE proteins; enzymes impacting serotonergic neurotransmission, and proteins affecting growth factor expression. NRG1 HET mice treated with THC expressed a distinct protein expression signature compared to WT mice. Replicating prior findings, THC caused proteomic changes in WT mice suggestive of greater oxidative stress and neurodegeneration. We have previously observed that THC selectively increased hippocampal NMDA receptor binding of adolescent NRG1 HET mice. Here we observed outcomes consistent with heightened NMDA-mediated glutamatergic neurotransmission. This included differential expression of proteins involved in NMDA receptor trafficking to the synaptic membrane; lipid raft stabilization of synaptic NMDA receptors; and homeostatic responses to dampen excitotoxicity. These findings uncover novel proteins altered in response to NRG1 hypomorphism and NRG1-cannabinoid interactions that improves our molecular understanding of NRG1 signaling and NRG1-mediated genetic vulnerability to the neurobehavioral effects of cannabinoids. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 344 | Schizophr. Res. 2013 Mar 144: 24-30 |
| PMID | 23360725 |
| Title | Association study of neuregulin-1 gene polymorphisms in a North Indian schizophrenia sample. |
| Abstract | Neuregulin-1 (NRG1) gene polymorphisms have been proposed as risk factors for several common disorders. Associations with cognitive variation have also been tested. With regard to schizophrenia (SZ) risk, studies of Caucasian ancestry samples indicate associations more consistently than East Asian samples, suggesting heterogeneity. To exploit the differences in linkage disequilibrium (LD) structure across ethnic groups, we conducted a SZ case-control study (that included cognitive evaluations) in a sample from the north Indian population. NRG1 variants (n=35 SNPs, three microsatellite markers) were initially analyzed among cases (DSM IV criteria, n=1007) and controls (n=1019, drawn from two groups) who were drawn from the same geographical region in North India. Nominally significant associations with SZ were next analyzed in relation to neurocognitive measures estimated with a computerized neurocognitive battery in a subset of the sample (n=116 cases, n=170 controls). Three variants and one microsatellite showed allelic association with SZ (rs35753505, rs4733263, rs6994992, and microsatellite 420M9-1395, p?0.05 uncorrected for multiple comparisons). A six marker haplotype 221121 (rs35753505-rs6994992-rs1354336-rs10093107-rs3924999-rs11780123) showed (p=0.0004) association after Bonferroni corrections. Regression analyses with the neurocognitive measures showed nominal (uncorrected) associations with emotion processing and attention at rs35753505 and rs6994992, respectively. Suggestive associations with SZ and SZ-related neurocognitive measures were detected with two SNPs from the NRG1 promoter region in a north Indian cohort. The functional role of the alleles merits further investigation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 345 | World J. Biol. Psychiatry 2013 Sep 14: 490-9 |
| PMID | 22424243 |
| Title | Gene expression of glutamate transporters SLC1A1, SLC1A3 and SLC1A6 in the cerebellar subregions of elderly schizophrenia patients and effects of antipsychotic treatment. |
| Abstract | The glutamatergic hypothesis of schizophrenia proposes alterations of excitatory amino acid transporters (solute carrier family, SLCs) expression and cerebellar dysfunctions. The influence of the neuregulin-1 (NRG1) risk genotype or effects of antipsychotics on expression of EAATs are unknown. We compared post-mortem samples from the cerebellar hemispheres and vermis of 10 schizophrenia patients with nine normal subjects by investigating gene expression of SLC1A3, SLC1A1 and SLC1A6 by in-situ hybridization. We further assessed the allelic composition regarding the polymorphism rs35753505 (SNP8NRG221533) near the NRG1 gene. To control for effects due to antipsychotic treatment, we chronically treated rats with the antipsychotics haloperidol or clozapine and assessed gene expression of SLCs. schizophrenia patients showed increased expression of SLC1A3 in the molecular layer of the vermis. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of SLC1A6 in the molecular layer of both hemispheres, compared to individuals homozygous for the T allele. The animal model revealed suppression of SLC1A6 by clozapine. Increased SLC1A3 expression indicates facilitated transport and may result in reduced glutamate neurotransmission. Decreased SLC1A6 expression in NRG1 risk variant may be an adaptive effect to restore glutamate signalling, but treatment effects cannot be excluded. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 346 | Int. J. Neuropsychopharmacol. 2013 Feb 16: 163-75 |
| PMID | 22226049 |
| Title | Transmembrane domain Nrg1 mutant mice show altered susceptibility to the neurobehavioural actions of repeated THC exposure in adolescence. |
| Abstract | Heavy cannabis abuse increases the risk of developing schizophrenia. Adolescents appear particularly vulnerable to the development of psychosis-like symptoms after cannabis use. To test whether the schizophrenia candidate gene neuregulin 1 (NRG1) modulates the effects of cannabinoids in adolescence, we tested male adolescent heterozygous transmembrane domain NRG1 mutant (NRG1 TM HET) mice and wild type-like littermates (WT) for their neurobehavioural response to repeated ?(9)-tetrahydrocannabinol (THC, 10 mg/kg i.p. for 21 d starting on post-natal day 31). During treatment and 48 h after treatment withdrawal, we assessed several behavioural parameters relevant to schizophrenia. After behavioural testing we measured autoradiographic CB(1), 5-HT(2A) and NMDA receptor binding. The hyperlocomotor phenotype typical of NRG1 mutants emerged after drug withdrawal and was more pronounced in vehicle than THC-treated NRG1 TM HET mice. All mice were equally sensitive to THC-induced suppression of locomotion. However, mutant mice appeared protected against inhibiting effects of repeated THC on investigative social behaviours. Neither THC nor NRG1 genotype altered prepulse inhibition. Repeated adolescent THC promoted differential effects on CB(1) and 5-HT(2A) receptor binding in the substantia nigra and insular cortex respectively, decreasing binding in WT while increasing it in NRG1 TM HET mice. THC also selectively affected 5-HT(2A) receptor binding in several other regions in WT mice, whereas NMDA receptor binding was only affected in mutant mice. Overall, NRG1 mutation does not appear to increase the induction of psychotomimetic symptoms by repeated adolescent THC exposure but may attenuate some of its actions on social behaviour and schizophrenia-relevant neurotransmitter receptor profiles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 347 | Neuron 2013 May 78: 644-57 |
| PMID | 23719163 |
| Title | Reversal of behavioral deficits and synaptic dysfunction in mice overexpressing neuregulin 1. |
| Abstract | Neuregulin 1 (NRG1) is a susceptibility gene of schizophrenia, a disabling mental illness that affects 1% of the general population. Here, we show that ctoNRG1 mice, which mimic high levels of NRG1 observed in forebrain regions of schizophrenic patients, exhibit behavioral deficits and hypofunction of glutamatergic and GABAergic pathways. Intriguingly, these deficits were diminished when NRG1 expression returned to normal in adult mice, suggesting that damage which occurred during development is recoverable. Conversely, increase of NRG1 in adulthood was sufficient to cause glutamatergic impairment and behavioral deficits. We found that the glutamatergic impairment by NRG1 overexpression required LIM domain kinase 1 (LIMK1), which was activated in mutant mice, identifying a pathological mechanism. These observations demonstrate that synaptic dysfunction and behavioral deficits in ctoNRG1 mice require continuous NRG1 abnormality in adulthood, suggesting that relevant schizophrenia may benefit from therapeutic intervention to restore NRG1 signaling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 348 | J. Pharmacol. Sci. 2013 -1 121: 185-91 |
| PMID | 23449491 |
| Title | Behavioral phenotypes in schizophrenic animal models with multiple combinations of genetic and environmental factors. |
| Abstract | schizophrenia is a multifactorial psychiatric disorder in which both genetic and environmental factors play a role. Genetic [e.g., Disrupted-in-schizophrenia 1 (DISC1), Neuregulin-1 (NRG1)] and environmental factors (e.g., maternal viral infection, obstetric complications, social stress) may act during the developmental period to increase the incidence of schizophrenia. In animal models, interactions between susceptibility genes and the environment can be controlled in ways not possible in humans; therefore, such models are useful for investigating interactions between or within factors in the pathogenesis and pathophysiology of schizophrenia. We provide an overview of schizophrenic animal models investigating interactions between or within factors. First, we reviewed gene-environment interaction animal models, in which schizophrenic candidate gene mutant mice were subjected to perinatal immune activation or adolescent stress. Next, environment-environment interaction animal models, in which mice were subjected to a combination of perinatal immune activation and adolescent administration of drugs, were described. These animal models showed interaction between or within factors; behavioral changes, which were obscured by each factor, were marked by interaction of factors and vice versa. Appropriate behavioral approaches with such models will be invaluable for translational research on novel compounds, and also for providing insight into the pathogenesis and pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 349 | Front Behav Neurosci 2014 -1 8: 455 |
| PMID | 25688191 |
| Title | Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia. |
| Abstract | Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1). Recent findings also revealed that NRG1 stimulates the PI3-kinase/AKT signaling pathway, which might be involved in the functional outcomes of some schizophrenic patients. The aim of this study was to evaluate the effect of Akt1-deficiency and NRG1-deficiency alone or in combination in the regulation of behavioral phenotypes, cognition, and social functions using genetically modified mice as a model. Male Akt1 (+/-), NRG1 (+/-), and double mutant mice were bred and compared with their wild-type (WT) littermate controls. In Experiment 1, general physical examination revealed that all mutant mice displayed a normal profile of body weight during development and a normal brain activity with microPET scan. In Experiment 2, no significant genotypic differences were found in our basic behavioral phenotyping, including locomotion, anxiety-like behavior, and sensorimotor gating function. However, both NRG1 (+/-) and double mutant mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In Experiment 3, a synergistic epistasis between Akt1 and NRG1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other 3 groups, especially encountering with a novel male or an ovariectomized female. Double mutant and NRG1 (+/-) mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of Akt1 and NRG1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 350 | Cell Commun. Signal 2014 -1 12: 47 |
| PMID | 25052836 |
| Title | TrkB interacts with ErbB4 and regulates NRG1-induced NR2B phosphorylation in cortical neurons before synaptogenesis. |
| Abstract | Neuregulin 1 (NRG1) and NMDARs play important roles in various neuronal functions including neural development. NMDARs also promote many cellular events such as proliferation and survival of neuroblasts before synapse formation. Although many recent studies have indicated that NRG1 regulates NMDAR function in cortical neurons, the effect of NRG1 on NMDAR activation before synapse formation is not well studied. NRG1 induces activation of NMDAR subunit NR2B, and tropomyosin-related kinase receptor B (TrkB), the receptor for BDNF via activation of phospholipase C-gamma (PLC-?) in immature primary cortical neurons. Our data using TrkB inhibitor (K252a), TrkB siRNA and TrkB-/- neurons demonstrated that TrkB inhibition suppresses NRG1-induced NR2B activation in neurons. We found that NRG1 stimulation leads to GABAA receptor-mediated TrkB activation. Co-immunoprecipitation and proximity ligase assay showed that TrkB interacts with ErbB4 (NRG1 receptor) and the TrkB-ErbB4 interaction was increased following NRG1 treatment. A significant reduction in TrkB-ErbB4 interaction was observed in the prefrontal cortex of schizophrenia subjects. We found significant increase in released BDNF levels following NRG1 treatment, which was inhibited by ErbB4 inhibitor, AG1478. In addition, pretreatment with BDNF neutralizing antibody, but not control IgG abolished NRG1-induced increases in phospho-TrkB and phospho-NR2B levels. Moreover, studies using TrkB mutants showed that intercellular domain of TrkB is necessary for TrkB-ErbB4 interaction and NR2B activation. BDNF/TrkB signaling plays an important role in the NRG1-stimulated NR2B regulation. These findings could be of relevance to many neurodevelopmental disorders, as NRG1 and BDNF signaling pathways have been implicated in autism and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 351 | Front Behav Neurosci 2014 -1 8: 126 |
| PMID | 24782733 |
| Title | Distinct phenotypes of new transmembrane-domain neuregulin 1 mutant mice and the rescue effects of valproate on the observed schizophrenia-related cognitive deficits. |
| Abstract | Accumulating evidence suggests that neuregulin 1 (NRG1) might be involved in the neurodevelopment, neural plasticity, GABAergic neurotransmission, and pathogenesis of schizophrenia. NRG1 is abundantly expressed in the hippocampus, and emerging studies have begun to reveal the link between NRG1 signaling and cognitive deficits in schizophrenic patients. Because the transmembrane domain of NRG1 is vital for both forward and reverse signaling cascades, new NRG1-deficient mice that carry a truncation of the transmembrane domain of the NRG1 gene were characterized and used in this study to test a NRG1 loss-of-function hypothesis for schizophrenia. Both male and female NRG1 heterozygous mutant mice and their wild-type littermates were used in a series of 4 experiments to characterize the impact of NRG1 on behavioral phenotypes and to determine the importance of NRG1 in the regulation of hippocampal neuromorphology and local GABAergic interneurons. First, a comprehensive battery of behavioral tasks indicated that male NRG1-deficient mice exhibited significant impairments in cognitive functions. Second, pharmacological challenges were conducted and revealed that NRG1 haploinsufficiency altered GABAergic activity in males. Third, although no genotype-specific neuromorphological alterations were found in the hippocampal CA1 pyramidal neurons, significant reductions in the hippocampal expressions of GAD67 and parvalbumin were revealed in the NRG1-deficient males. Fourth, chronic treatment with valproate rescued the observed behavioral deficits and hippocampal GAD67 reduction in NRG1-deficient males. Collectively, these results indicate the potential therapeutic effect of valproate and the importance of NRG1 in the regulation of cognitive functions and hippocampal GABAergic interneurons, especially in males. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 352 | Neuron 2014 Nov 84: 835-46 |
| PMID | 25451196 |
| Title | Maintenance of GABAergic activity by neuregulin 1-ErbB4 in amygdala for fear memory. |
| Abstract | Inhibitory neurotransmission in amygdala is important for fear learning and memory. However, mechanisms that control the inhibitory activity in amygdala are not well understood. We provide evidence that neuregulin 1 (NRG1) and its receptor ErbB4 tyrosine kinase are critical for maintaining GABAergic activity in amygdala. Neutralizing endogenous NRG1, inhibition, or genetic ablation of ErbB4, which was expressed in a majority of palvalbumin (PV)+ neurons in amygdala, reduced GABAergic transmission and inhibited tone-cued fear conditioning. Specific ablation of ErbB4 in PV+ neurons reduced eIPSC/eEPSC ratios and impaired fear conditioning. Notably, expression of ErbB4 in amygdala was sufficient to diminish synaptic dysfunction and fear conditioning deficits in PV-ErbB4-/- mice. These observations indicated that NRG1 signaling maintains high GABAergic activity in amygdala and, thus, regulates fear memory. Considering that both NRG1 and ErbB4 are susceptibility genes of schizophrenia, our study sheds light on potential pathophysiological mechanisms of this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 353 | J Psychiatr Res 2014 Oct 57: 84-9 |
| PMID | 25043418 |
| Title | Molecular evolution in the CREB1 signal pathway and a rare haplotype in CREB1 with genetic predisposition to schizophrenia. |
| Abstract | CREB1 is a cAMP responsive transcriptional factor which plays a key role in neural development. CREB1 signal pathway (CSP) has been implicated repeatedly in studies of predisposition for schizophrenia. We speculated that CSP has undergone positive selection during evolution of modern human and some genes that have undergone natural selection in the past may predispose to schizophrenia (SCZ) in modern time. Positive selection and association analysis were employed to explore the molecular evolution of CSP and association with schizophrenia. Our results showed a pan-ethnic selection event on NRG1 and CREB1, as confirmed in all 14 ethnic populations studied, which also suggested a selection process occurred before the "Out of Africa" scenario. Analysis of 62 SNPs covering 6 CSP genes in 2019 Han Chinese (976 SCZ patients and 1043 healthy individuals) showed an association of two SNPs (rs4379857, P = 0.009, OR [95% CI]: 1.200 [1.379-1.046]; rs2238751, P = 0.023, OR [95% CI]: 1.253 [1.522-1.032]) with SCZ. However, none of these significances survived after multiple testing corrections. Nonetheless, we observed an association of a rare CREB1 haplotype CCGGC (Bonferroni corrected P = 1.74 × 10(-5)) with SCZ. Our study showed that there was substantial population heterogeneity in genetic predisposition to SCZ, and different genes in the CSP pathway may predispose to SCZ in different populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 354 | PLoS ONE 2014 -1 9: e104172 |
| PMID | 25093331 |
| Title | Transient overexposure of neuregulin 3 during early postnatal development impacts selective behaviors in adulthood. |
| Abstract | Neuregulin 3 (NRG3), a specific ligand for ErbB4 and a neuronal-enriched neurotrophin is implicated in the genetic predisposition to a broad spectrum of neurodevelopmental, neurocognitive and neuropsychiatric disorders, including Alzheimer's disease, autism and schizophrenia. Genetic studies in schizophrenia demonstrate that risk variants in NRG3 are associated with cognitive and psychotic symptom severity, accompanied by increased expression of prefrontal cortical NRG3. Despite our expanding knowledge of genetic involvement of NRG3 in neurological disorders, little is known about the neurodevelopmental mechanisms of risk. Here we exploited the fact that a paralog of NRG3, NRG1, readily penetrates the murine blood brain barrier (BBB). In this study we synthesized the bioactive epidermal growth factor (EGF) domain of NRG3, and using previously validated in-vivo peripheral injection methodologies in neonatal mice, demonstrate that NRG3 successfully crosses the BBB, where it activates its receptor ErbB4 and downstream Akt signaling at levels of bioactivity comparable to NRG1. To determine the impact of NRG3 overexpression during one critical developmental window, C57BL/6 male mice were subcutaneously injected daily with NRG1-EGF, NRG3-EGF or vehicle from postnatal days 2-10. Mice were tested in adulthood using a comprehensive battery of behavioral tasks relevant to neurocognitive and psychiatric disorders. In agreement with previous studies, developmental overexposure to NRG1 induced multiple non-CNS mediated peripheral effects as well as severely disrupting performance of prepulse inhibition of the startle response. In contrast, NRG3 had no effect on any peripheral measures investigated or sensorimotor gating. Specifically, developmental NRG3 overexposure produced an anxiogenic-like phenotype and deficits in social behavior in adulthood. These results provide primary data to support a role for NRG3 in brain development and function, which appears to be distinct from its paralog NRG1. Furthermore we demonstrate how perturbations in NRG3 expression at distinct developmental stages may contribute to the neurological deficits observed in brain disorders such as schizophrenia and autism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 355 | Cell Rep 2014 Aug 8: 1130-45 |
| PMID | 25131210 |
| Title | Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity. |
| Abstract | Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an "optimal" level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 356 | Asian J Psychiatr 2014 Aug 10: 62-8 |
| PMID | 25042954 |
| Title | An exploratory association study of the influence of dysbindin and neuregulin polymorphisms on brain morphometry in patients with schizophrenia and healthy subjects from South India. |
| Abstract | Multiple genetic risk variants may act in a convergent manner leading on to the pathophysiological alterations of brain structure and function in schizophrenia. We examined the effect of polymorphisms of two candidate genes that mediate glutamatergic signaling, viz., dysbindin (rs1011313) and neuregulin (rs35753505), on brain morphometry in patients with schizophrenia (N=38) and healthy subjects (N=37) from South India. Patients with schizophrenia showed trend-level (p<0.001 uncorrected, 20 voxel extent correction) volumetric reductions in multiple brain regions when compared to healthy control subjects. Trend-level volumetric differences were also noted between homozygotes of the risk allele (AA) of the neuregulin (NRG1) polymorphism and heterozygotes (AG), as well as homozygotes of the risk allele (CC) of the dysbindin (DTNBP1) polymorphism and heterozygotes (TC), irrespective of diagnosis. Moreover, an additive effect of the risk alleles on brain morphometry was also noted. These preliminary findings highlight the possible influence of polymorphisms of risk genes on brain morphometry in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 357 | Prog. Brain Res. 2014 -1 211: 79-112 |
| PMID | 24968777 |
| Title | Dopaminergic function in relation to genes associated with risk for schizophrenia: translational mutant mouse models. |
| Abstract | Mutant mice play an increasingly important role in understanding disease processes at multiple levels. In particular, they illuminate the impact of risk genes for disease on such processes. This article reviews recent advances in the application of mutant mice to study the intricacies of dopaminergic (DAergic) function in relation to the putative pathophysiology of psychotic illness, particularly schizophrenia, and antipsychotic drug action. It considers models for understanding the role(s) of risk genes, with a particular focus on DTNBP1 and NRG1, their interactions with environmental factors, and with each other (epistasis). In overview, it considers new schemas for understanding psychotic illness that integrate DAergic pathophysiology with developmental, social, and cognitive processes, and how mutant mouse models can reflect and inform on such schemas. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 358 | Elife 2014 -1 3: -1 |
| PMID | 24891237 |
| Title | Cell autonomous regulation of hippocampal circuitry via Aph1b-?-secretase/neuregulin 1 signalling. |
| Abstract | Neuregulin 1 (NRG1) and the ?-secretase subunit APH1B have been previously implicated as genetic risk factors for schizophrenia and schizophrenia relevant deficits have been observed in rodent models with loss of function mutations in either gene. Here we show that the Aph1b-?-secretase is selectively involved in NRG1 intracellular signalling. We found that Aph1b-deficient mice display a decrease in excitatory synaptic markers. Electrophysiological recordings show that Aph1b is required for excitatory synaptic transmission and plasticity. Furthermore, gain and loss of function and genetic rescue experiments indicate that NRG1 intracellular signalling promotes dendritic spine formation downstream of Aph1b-?-secretase in vitro and in vivo. In conclusion, our study sheds light on the physiological role of Aph1b-?-secretase in brain and provides a new mechanistic perspective on the relevance of NRG1 processing in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 359 | J. Neurosci. 2014 Oct 34: 13549-66 |
| PMID | 25274830 |
| Title | Genetic labeling reveals novel cellular targets of schizophrenia susceptibility gene: distribution of GABA and non-GABA ErbB4-positive cells in adult mouse brain. |
| Abstract | Neuregulin 1 (NRG1) and its receptor ErbB4 are schizophrenia risk genes. NRG1-ErbB4 signaling plays a critical role in neural development and regulates neurotransmission and synaptic plasticity. Nevertheless, its cellular targets remain controversial. ErbB4 was thought to express in excitatory neurons, although recent studies disputed this view. Using mice that express a fluorescent protein under the promoter of the ErbB4 gene, we determined in what cells ErbB4 is expressed and their identity. ErbB4 was widely expressed in the mouse brain, being highest in amygdala and cortex. Almost all ErbB4-positive cells were GABAergic in cortex, hippocampus, basal ganglia, and most of amygdala in neonatal and adult mice, suggesting GABAergic transmission as a major target of NRG1-ErbB4 signaling in these regions. Non-GABAergic, ErbB4-positive cells were present in thalamus, hypothalamus, midbrain, and hindbrain. In particular, ErbB4 is expressed in serotoninergic neurons of raphe nuclei but not in norepinephrinergic neurons of the locus ceruleus. In hypothalamus, ErbB4 is present in neurons that express oxytocin. Finally, ErbB4 is expressed in a group of cells in the subcortical areas that are positive for S100 calcium binding protein ?. These results identify novel cellular targets of NRG1-ErbB4 signaling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 360 | Neuromolecular Med. 2014 Dec 16: 742-51 |
| PMID | 25142529 |
| Title | No association between NRG1 and ErbB4 genes and psychopathological symptoms of schizophrenia. |
| Abstract | Neuregulin 1 (NRG1) and v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) have been extensively studied in schizophrenia susceptibility because of their pivotal role in key neurodevelopmental processes. One of the reasons for the inconsistencies in results could be the fact that the phenotype investigated has mostly the diagnosis of schizophrenia per se, which is widely heterogeneous, both clinically and biologically. In the present study we tested, in a large cohort of 461 schizophrenia patients recruited in Scotland, whether several SNPs in NRG1 and/or ErbB4 are associated with schizophrenia symptom dimensions as evaluated by the Positive and Negative Syndrome Scale (PANSS). We then followed up nominally significant results in a second cohort of 439 schizophrenia subjects recruited in Germany. Using linear regression, we observed two different groups of polymorphisms in NRG1 gene: one showing a nominal association with higher scores of the PANSS positive dimension and the other one with higher scores of the PANSS negative dimension. Regarding ErbB4, a small cluster located in the 5' end of the gene was detected, showing nominal association mainly with negative, general and total dimensions of the PANSS. These findings suggest that some regions of NRG1 and ErbB4 are functionally involved in biological processes that underlie some of the phenotypic manifestations of schizophrenia. Because of the lack of significant association after correction for multiple testing, our analyses should be considered as exploratory and hypothesis generating for future studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 361 | Neuroscience 2014 Mar 261: 107-17 |
| PMID | 24374327 |
| Title | Neuregulin 1/ErbB4 enhances synchronized oscillations of prefrontal cortex neurons via inhibitory synapses. |
| Abstract | Both neuregulin 1 (NRG1) and its receptor ErbB4 are susceptibility genes for schizophrenia. Reduced synchronization of evoked oscillations in several cortical regions, especially in the prefrontal cortex, is associated with the core symptoms of schizophrenia. Recent studies have reported that NRG1 may affect the hippocampal oscillations. However, the role of NRG1/ErbB4 signaling in the synchronization of neurons in the prefrontal cortex is unclear. Here, we found that NRG1 enhanced the synchrony of pyramidal neurons via presynaptic interneurons. Meanwhile, NRG1 also increased the synchrony between pairs of fast-spiking interneurons and pairs of fast-spiking and non-fast-spiking interneurons in the prefrontal cortex, and this effect was mediated by ErbB4 receptors. Moreover, the NRG1-enhanced synchrony of interneurons was through their mutually-inhibitory synapses but not electrical coupling. Furthermore, kainate-induced gamma oscillations in vivo were enhanced by NRG1 and did not change in Dlx5/6-ErbB4(-/-) mice in which the ErbB4 receptors were specifically knocked out in interneurons of the frontal brain. Overall, our findings suggested that NRG1/ErbB4 signaling plays an important role in the synchronized oscillations of the whole network in the prefrontal cortex that are impaired in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 362 | J Psychiatr Res 2014 Jun 53: 125-32 |
| PMID | 24636039 |
| Title | Elevated ErbB4 mRNA is related to interneuron deficit in prefrontal cortex in schizophrenia. |
| Abstract | Neuregulin 1 and its receptor ErbB4 are confirmed risk genes for schizophrenia, but the neuropathological alterations in NRG1-ErbB4 in schizophrenia are unclear. The present investigations therefore focused on determining lamina specific (ErbB4-pan) and quantitative (pan, JMa, JMb, CYT1 and CYT2) ErbB4 mRNA changes in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. We also determined which neuronal profiles are ErbB4 mRNA+ in the human DLPFC and the relationship between ErbB4 and interneuron marker mRNAs. In situ hybridisation and quantitative PCR measurements were performed to determine changes in ErbB4 splice variant mRNA levels in the DLPFC in schizophrenia (n = 37) compared to control (n = 37) subjects. Cortical neurons expressing ErbB4-pan were labelled with silver grain clusters. Correlations were performed between ErbB4 and interneuron mRNA levels. ErbB4-pan mRNA was significantly increased (layers I, II and V) in the DLPFC in schizophrenia. Silver grain clusters for ErbB4-pan were detected predominantly over small-medium neurons with low-no expression in the larger, paler, more triangular neuronal profiles. ErbB4-JMa mRNA expression was increased in schizophrenia. Somatostatin, neuropeptide Y and vasoactive intestinal peptide mRNAs negatively correlated with ErbB4-JMa mRNA in people with schizophrenia. Our findings demonstrate that ErbB4-pan laminar mRNA expression is elevated (layers I, II, V) in schizophrenia. At the cellular level, ErbB4-pan mRNA+ signal was detected predominantly in interneuron-like neurons. We provide evidence from this independent Australian postmortem cohort that ErbB4-JMa expression is elevated in schizophrenia and is linked to deficits in dendrite-targeting somatostatin, neuropeptide Y and vasoactive intestinal peptide interneurons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 363 | J Neural Transm (Vienna) 2014 May 121: 479-90 |
| PMID | 24380930 |
| Title | Global signaling effects of a schizophrenia-associated missense mutation in neuregulin 1: an exploratory study using whole genome and novel kinome approaches. |
| Abstract | Aberrant neuregulin 1-ErbB4 signaling has been implicated in schizophrenia. We previously identified a novel schizophrenia-associated missense mutation (valine to leucine) in the NRG1 transmembrane domain. This variant inhibits formation of the NRG1 intracellular domain (ICD) and causes decreases in dendrite formation. To assess the global effects of this mutation, we used lymphoblastoid cell lines from unaffected heterozygous carriers (Val/Leu) and non-carriers (Val/Val). Transcriptome data showed 367 genes differentially expressed between the two groups (Val/Val N = 6, Val/Leu N = 5, T test, FDR (1 %), ? = 0.05, -log10 p value >1.5). Ingenuity pathway (IPA) analyses showed inflammation and NRG1 signaling as the top pathways altered. Within NRG1 signaling, protein kinase C (PKC)-eta (PRKCH) and non-receptor tyrosine kinase (SRC) were down-regulated in heterozygous carriers. Novel kinome profiling (serine/threonine) was performed after stimulating cells (V/V N = 6, V/L N = 6) with ErbB4, to induce release of the NRG1 ICD, and revealed significant effects of treatment on the phosphorylation of 35 peptides. IPA showed neurite outgrowth (six peptides) as the top annotated function. Phosphorylation of these peptides was significantly decreased in ErbB4-treated Val/Val but not in Val/Leu cells. These results show that perturbing NRG1 ICD formation has major effects on cell signaling, including inflammatory and neurite formation pathways, and may contribute significantly to schizophrenia pathophysiology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 364 | Seishin Shinkeigaku Zasshi 2014 -1 116: 842-58 |
| PMID | 25672211 |
| Title | [Role of oxidative stress in the pathophysiology of neuropsychiatric disorders]. |
| Abstract | The brain is particularly vulnerable to oxidative damage because of its high rate of oxygen consumption, abundant lipid content, and relative paucity of antioxidant enzymes compared with other organs. It has been well established that oxidative stress (OS) is involved in the pathogenesis of age-associated neurodegenerative disorders such as Alzheimer's disease (AD). Indeed, a large number of genetic and environmental factors of neurodegenerative disorders are associated with OS. Of note, studies on the levels of oxidative damage in patients with the prodromal stage of AD, transgenic animal models of AD, and induced pluripotent stem (iPS) cells derived from AD patients support the early-stage involvement of OS in the pathological cascade of the disorder. Recently, a growing body of evidence suggests that a considerable number of genetic and environmental factors of psychiatric disorders such as schizophrenia (SZ), bipolar disorders, and depression are associated with OS. Not only genetic polymorphisms in genes encoding antioxidant enzymes but also several known susceptible genes for psychiatric disorders, i. e., Disrupted-in-schizophrenia-1 (DISC1), Neuregulin 1 (NRG1), proline dehydrogenase (PRODH), and G72, are all associated with increased levels of OS or decreased antioxidant capacities. Moreover, environmental factors such as infection, hypoxia, malnutrition, illicit substance use, and psychosocial stress are possibly associated with OS. In fact, increased levels of oxidized nucleic acids, proteins, and lipids have been described in the postmortem brains of patients with SZ and bipolar disorders, and decreased antioxidant capacities have been described in blood samples obtained from patients with first-episode psychosis. In concordance, iPS cells from SZ patients show an increased level of OS. Of particular interest is a conditional gene knockout mouse model of SZ with the functional elimination of NMDA receptors specifically from cortical interneurons. The NMDA receptor knockout mouse shows behavioral phenotypes resembling symptoms of human SZ. Importantly, a marked increase of OS, particularly in the cortical parvalbumin-positive interneurons, is rapidly exacerbated by post-weaning social isolation, but treatment with antioxidants abolishes OS and partially alleviates the SZ-like behavioral phenotypes. Therefore, it is suggested that OS is a convergence point for genetic and environmental susceptibilities to not only neurodegenerative but also psychiatric disorders. In other words, OS potentially plays a central role in the pathomechanisms that integrate gene-environment interactions in neuropsychiatric disorders. Further investigations into the development of useful OS biomarkers and efficacious OS-targeting interventions may shed light on a promising approach for establishing preemptive strategies against neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 365 | Ann Neurosci 2014 Oct 21: 138-43 |
| PMID | 25452674 |
| Title | Study of five novel non-synonymous polymorphisms in human brain-expressed genes in a Colombian sample. |
| Abstract | Non-synonymous single nucleotide polymorphisms (nsSNPs) in brain-expressed genes represent interesting candidates for genetic research in neuropsychiatric disorders. To study novel nsSNPs in brain-expressed genes in a sample of Colombian subjects. We applied an approach based on in silico mining of available genomic data to identify and select novel nsSNPs in brain-expressed genes. We developed novel genotyping assays, based in allele-specific PCR methods, for these nsSNPs and genotyped them in 171 Colombian subjects. Five common nsSNPs (rs6855837; p.Leu395Ile, rs2305160; p.Thr394Ala, rs10503929; p.Met289Thr, rs2270641; p.Thr4Pro and rs3822659; p.Ser735Ala) were studied, located in the CLOCK, NPAS2, NRG1, SLC18A1 and WWC1 genes. We reported allele and genotype frequencies in a sample of South American healthy subjects. There is previous experimental evidence, arising from genome-wide expression and association studies, for the involvement of these genes in several neuropsychiatric disorders and endophenotypes, such as schizophrenia, mood disorders or memory performance. Frequencies for these nsSNPSs in the Colombian samples varied in comparison to different HapMap populations. Future study of these nsSNPs in brain-expressed genes, a synaptogenomics approach, will be important for a better understanding of neuropsychiatric diseases and endophenotypes in different populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 366 | Front Behav Neurosci 2014 -1 8: 298 |
| PMID | 25324742 |
| Title | Partial genetic deletion of neuregulin 1 and adolescent stress interact to alter NMDA receptor binding in the medial prefrontal cortex. |
| Abstract | schizophrenia is thought to arise due to a complex interaction between genetic and environmental factors during early neurodevelopment. We have recently shown that partial genetic deletion of the schizophrenia susceptibility gene neuregulin 1 (NRG1) and adolescent stress interact to disturb sensorimotor gating, neuroendocrine activity and dendritic morphology in mice. Both stress and NRG1 may have converging effects upon N-methyl-D-aspartate receptors (NMDARs) which are implicated in the pathogenesis of schizophrenia, sensorimotor gating and dendritic spine plasticity. Using an identical repeated restraint stress paradigm to our previous study, here we determined NMDAR binding across various brain regions in adolescent NRG1 heterozygous (HET) and wild-type (WT) mice using [(3)H] MK-801 autoradiography. Repeated restraint stress increased NMDAR binding in the ventral part of the lateral septum (LSV) and the dentate gyrus (DG) of the hippocampus irrespective of genotype. Partial genetic deletion of NRG1 interacted with adolescent stress to promote an altered pattern of NMDAR binding in the infralimbic (IL) subregion of the medial prefrontal cortex. In the IL, whilst stress tended to increase NMDAR binding in WT mice, it decreased binding in NRG1 HET mice. However, in the DG, stress selectively increased the expression of NMDAR binding in NRG1 HET mice but not WT mice. These results demonstrate a NRG1-stress interaction during adolescence on NMDAR binding in the medial prefrontal cortex. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 367 | CNS Neurol Disord Drug Targets 2014 -1 13: 1604-14 |
| PMID | 25106628 |
| Title | Drugs targeting SNPrs35753505 of the NRG1 gene may prevent the association of neurological disorder schizophrenia in a Pakistani population. |
| Abstract | The Neuregulin 1 (NRG1) gene has been associated with schizophrenia in several populations, and all four types of NRG1 genes are linked with neurotransmitters activities. In this study for the first time we have demonstrated an association between NRG1 mutation and schizophrenia in Pakistani population. We examined the relationship of three genetic variants SNPs: rs3924999, rs2954041 and rs35753505 of NRG1 gene with the onset of disease. Genomic DNA samples were obtained from the blood of 100 patients and 80 matched controls. All three NRG1 SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism method and further confirmed by DNA sequencing. The SNPs frequencies were estimated by Hardy-Weinberg equilibrium and Chi-square tests. Our study established a significant association of rs35753505 with schizophrenia but no association with rs3924999 and rs2954041. The frequency of risk allele C was significantly higher (62.5%) in rs35753505 patients when compared to controls (28.13%). Genotype frequency by Hardy-Weinberg equilibrium for SNPrs3924999 in patients was GG 77.4%, GA 21.12% and AA 1.44% and showed no association with the disease. Similarly, no genotype association was observed in rs2954041: GG 92.98%, GT 6.89%, TT 0.13% of NRG1. However, one unexpected G allele, 100% guanine (G) with no adenine (A) was found to be present in SNP rs35753505 in both patients and controls. This is an interesting finding that both cohorts display only allele G peak but no peak for allele A in the electropherogram for this SNP. Our results suggest that SNP rs35753505 of NRG1 plays an important role in conferring susceptibility to the schizophrenia in a Pakistani population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 368 | Ann Gen Psychiatry 2014 -1 13: 18 |
| PMID | 24976857 |
| Title | Cognitive outcome and gamma noise power unrelated to neuregulin 1 and 3 variation in schizophrenia. |
| Abstract | Neuregulins are a family of signalling proteins that orchestrate a broad range of cellular responses. Four genes encoding Neuregulins 1-4 have been identified so far in vertebrates. Among them, Neuregulin 1 and Neuregulin 3 have been reported to contribute to an increased risk for developing schizophrenia. We hypothesized that three specific variants of these genes (rs6994992 and rs3924999 for Neuregulin 1 and rs10748842 for Neuregulin 3) that have been related to this illness may modify information processing capacity in the cortex, which would be reflected in electrophysiological parameters (P3b amplitude or gamma noise power) and/or cognitive performance. We obtained DNA from 31 patients with schizophrenia and 23 healthy controls and analyzed NRG1 rs6994992, NRG1 rs3924999 and NRG3 rs10748842 promoter polymorphisms by allelic discrimination with real-time polymerase chain reaction (PCR). We compared cognitive outcome, P300 amplitude parameters and an electroencephalographic measure of noise power in the gamma band between the groups dichotomized according to genotype. Contrary to our hypothesis, we could not detect any significant influence of variation in Neuregulin 1/Neuregulin 3 polymorphisms on cognitive performance or electrophysiological parameters of patients with schizophrenia. Despite our findings, we cannot discard that other genetic variants and, more likely, interactions between those variants and with genetic variation related to different pathways may still influence cerebral processing in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 369 | Neuroscience 2014 Sep 277: 294-305 |
| PMID | 24969132 |
| Title | Phenotypic effects of maternal immune activation and early postnatal milieu in mice mutant for the schizophrenia risk gene neuregulin-1. |
| Abstract | Risk of schizophrenia is likely to involve gene × environment (G × E) interactions. Neuregulin 1 (NRG1) is a schizophrenia risk gene, hence any interaction with environmental adversity, such as maternal infection, may provide further insights into the basis of the disease. This study examined the individual and combined effects of prenatal immune activation with polyriboinosinic-polyribocytidilic acid (Poly I:C) and disruption of the schizophrenia risk gene NRG1 on the expression of behavioral phenotypes related to schizophrenia. NRG1 heterozygous (NRG1 HET) mutant breeding pairs were time-mated. Pregnant dams received a single injection (5mg/kg i.p.) of Poly I:C or vehicle on gestation day 9 (GD9). Offspring were then cross-fostered to vehicle-treated or Poly I:C-treated dams. Expression of schizophrenia-related behavioral endophenotypes was assessed at adolescence and in adulthood. Combining NRG1 disruption and prenatal environmental insult (Poly I:C) caused developmental stage-specific deficits in social behavior, spatial working memory and prepulse inhibition (PPI). However, combining Poly I:C and cross-fostering produced a number of behavioral deficits in the open field, social behavior and PPI. This became more complex by combining NRG1 deletion with both Poly I:C exposure and cross-fostering, which had a robust effect on PPI. These findings suggest that concepts of G × E interaction in risk of schizophrenia should be elaborated to multiple interactions that involve individual genes interacting with diverse biological and psychosocial environmental factors over early life, to differentially influence particular domains of psychopathology, sometimes over specific stages of development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 370 | Am J Psychiatry 2014 Sep 171: 979-89 |
| PMID | 24935406 |
| Title | Effects of schizophrenia risk variation in the NRG1 gene on NRG1-IV splicing during fetal and early postnatal human neocortical development. |
| Abstract | Neuregulin 1 (NRG1) is a multifunctional neurotrophin that mediates neurodevelopment and schizophrenia risk. The NRG1 gene undergoes extensive alternative splicing, and association of brain NRG1 type IV isoform expression with the schizophrenia-risk polymorphism rs6994992 is a potential mechanism of risk. Novel splice variants of NRG1-IV (NRG1-IVNV), with predicted unique signaling capabilities, have been cloned in fetal brain tissue. The authors investigated the temporal dynamics of transcription of NRG1-IVNV, compared with the major NRG1 isoforms, across human prenatal and postnatal prefrontal cortical development, and they examined the association of rs6994992 with NRG1-IVNV expression. NRG1 type I-IV and NRG1-IVNV isoforms were evaluated with quantitative real-time polymerase chain reaction in human postmortem prefrontal cortex tissue samples at 14 to 39 weeks gestation and postnatal ages 0-83 years. The association of rs6994992 genotype with NRG1-IVNV expression and the subcellular distribution and proteolytic processing of NRG1-IVNV isoforms were also determined. Expression of NRG1 types I, II, and III was temporally regulated during prenatal and postnatal neocortical development. NRG1-IVNV was expressed from 16 weeks gestation until age 3. Homozygosity for the schizophrenia risk allele (T) of rs6994992 conferred lower cortical NRG1-IVNV levels. Assays showed that NRG1-IVNV is a novel nuclear-enriched, truncated NRG1 protein resistant to proteolytic processing. To the authors' knowledge, this study provides the first quantitative map of NRG1 isoform expression during human neocortical development and aging. It identifies a potential mechanism of early developmental risk for schizophrenia at the NRG1 locus, involving a novel class of NRG1 proteins. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 371 | Genes Brain Behav. 2014 Sep 13: 713-20 |
| PMID | 24920375 |
| Title | Do individually ventilated cage systems generate a problem for genetic mouse model research? |
| Abstract | Technological developments over recent decades have produced a novel housing system for laboratory mice, so-called 'individually ventilated cage' (IVC) systems. IVCs present a cage environment which is different to conventional filter-top cages (FILTER). Nothing is known about the consequences of IVC housing on genetic mouse models, despite studies reporting IVC-mediated changes to the phenotypes of inbred mouse strains. Thus, in this study, we systematically compared the established behavioural phenotype of a validated mouse model for the schizophrenia risk gene neuregulin 1 (TM NRG1 HET) kept in FILTER housing with NRG1 mutant mice raised in IVC systems. We found that particular schizophrenia-relevant endophenotypes of TM NRG1 HETs which had been established and widely published using FILTER housing were altered when mice were raised in IVC housing. IVCs diminished the schizophrenia-relevant prepulse inhibition deficit of NRG1 mutant males. Furthermore, IVC housing had a sex-dependent moderate effect on the locomotive phenotype of NRG1 mice across test paradigms. Behavioural effects of IVC housing were less prominent in female mice. Thus, transferring the breeding colony of mouse mutants from FILTER to IVC systems can shift disease-relevant behaviours and therefore challenge the face validity of these mice. Researchers facing an upgrade of their mouse breeding or holding facilities to IVC systems must be aware of the potential impact this upgrade might have on their genetic mouse models. Future publications should provide more details on the cage system used to allow appropriate data comparison across research sites. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 372 | Transl Psychiatry 2014 -1 4: e392 |
| PMID | 24865593 |
| Title | Schizophrenia-risk variant rs6994992 in the neuregulin-1 gene on brain developmental trajectories in typically developing children. |
| Abstract | The neuregulin-1 (NRG1) gene is one of the best-validated risk genes for schizophrenia, and psychotic and bipolar disorders. The rs6994992 variant in the NRG1 promoter (SNP8NRG243177) is associated with altered frontal and temporal brain macrostructures and/or altered white matter density and integrity in schizophrenic adults, as well as healthy adults and neonates. However, the ages when these changes begin and whether neuroimaging phenotypes are associated with cognitive performance are not fully understood. Therefore, we investigated the association of the rs6994992 variant on developmental trajectories of brain macro- and microstructures, and their relationship with cognitive performance. A total of 972 healthy children aged 3-20 years had the genotype available for the NRG1-rs6994992 variant, and were evaluated with magnetic resonance imaging (MRI) and neuropsychological tests. Age-by-NRG1-rs6994992 interactions and genotype effects were assessed using a general additive model regression methodology, covaried for scanner type, socioeconomic status, sex and genetic ancestry factors. Compared with the C-carriers, children with the TT-risk-alleles had subtle microscopic and macroscopic changes in brain development that emerge or reverse during adolescence, a period when many psychiatric disorders are manifested. TT-children at late adolescence showed a lower age-dependent forniceal volume and lower fractional anisotropy; however, both measures were associated with better episodic memory performance. To our knowledge, we provide the first multimodal imaging evidence that genetic variation in NRG1 is associated with age-related changes on brain development during typical childhood and adolescence, and delineated the altered patterns of development in multiple brain regions in children with the T-risk allele(s). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 373 | Brain Behav 2014 Mar 4: 215-26 |
| PMID | 24683514 |
| Title | A Neuregulin-1 schizophrenia susceptibility variant causes perihippocampal fiber tract anomalies in healthy young subjects. |
| Abstract | Changes in fiber tract architecture have gained attention as a potentially important aspect of schizophrenia neuropathology. Although the exact pathogenesis of these abnormalities yet remains to be elucidated, a genetic component is highly likely. Neuregulin-1 (NRG1) is one of the best-validated schizophrenia susceptibility genes. We here report the impact of the Neuregulin-1 rs35753505 variant on white matter structure in healthy young individuals with no family history of psychosis. We compared fractional anisotropy in 54 subjects that were either homozygous for the risk C allele carriers (n?=?31) for rs35753505 or homozygous for the T allele (n?=?23) using diffusion tensor imaging with 3T. Tract-Based Spatial Statistics (TBSS), a method especially developed for diffusion data analysis, was used to improve white matter registration and to focus the statistical analysis to major fiber tracts. Statistical analysis showed that homozygous risk C allele carriers featured elevated fractional anisotropy (FA) in the right perihippocampal region and the white matter proximate to the left area 4p as well as the right hemisphere of the cerebellum. We found three clusters of reduced FA values in homozygous C allele carriers: in the left superior parietal region, the right prefrontal white matter and in the deep white matter of the left frontal lobe. Our results highlight the importance of Neuregulin-1 for structural connectivity of the right medial temporal lobe. This finding is in line with well known neuropathological findings in this region in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 374 | JAMA Psychiatry 2014 May 71: 531-9 |
| PMID | 24622944 |
| Title | Striatal response to reward anticipation: evidence for a systems-level intermediate phenotype for schizophrenia. |
| Abstract | Attenuated ventral striatal response during reward anticipation is a core feature of schizophrenia that is seen in prodromal, drug-naive, and chronic schizophrenic patients. schizophrenia is highly heritable, raising the possibility that this phenotype is related to the genetic risk for the disorder. To examine a large sample of healthy first-degree relatives of schizophrenic patients and compare their neural responses to reward anticipation with those of carefully matched controls without a family psychiatric history. To further support the utility of this phenotype, we studied its test-retest reliability, its potential brain structural contributions, and the effects of a protective missense variant in neuregulin 1 (NRG1) linked to schizophrenia by meta-analysis (ie, rs10503929). Examination of a well-established monetary reward anticipation paradigm during functional magnetic resonance imaging at a university hospital; voxel-based morphometry; test-retest reliability analysis of striatal activations in an independent sample of 25 healthy participants scanned twice with the same task; and imaging genetics analysis of the control group. A total of 54 healthy first-degree relatives of schizophrenic patients and 80 controls matched for demographic, psychological, clinical, and task performance characteristics were studied. Blood oxygen level-dependent response during reward anticipation, analysis of intraclass correlations of functional contrasts, and associations between striatal gray matter volume and NRG1 genotype. Compared with controls, healthy first-degree relatives showed a highly significant decrease in ventral striatal activation during reward anticipation (familywise error-corrected P?.05), and affected by the NRG1 genotype (higher striatal responses in controls with the protective rs10503929 C allele; familywise error-corrected P?Healthy first-degree relatives of schizophrenic patients show altered striatal activation during reward anticipation in a directionality and localization consistent with prior patient findings. This provides evidence for a functional neural system mechanism related to familial risk. The phenotype can be assessed reliably, is independent of alterations in striatal structure, and is influenced by a schizophrenia candidate gene variant in NRG1. These data encourage us to further investigate the genetic and molecular contributions to this phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 375 | Schizophr Bull 2014 Nov 40: 1272-84 |
| PMID | 24442851 |
| Title | Partial genetic deletion of neuregulin 1 modulates the effects of stress on sensorimotor gating, dendritic morphology, and HPA axis activity in adolescent mice. |
| Abstract | Stress has been linked to the pathogenesis of schizophrenia. Genetic variation in neuregulin 1 (NRG1) increases the risk of developing schizophrenia and may help predict which high-risk individuals will transition to psychosis. NRG1 also modulates sensorimotor gating, a schizophrenia endophenotype. We used an animal model to demonstrate that partial genetic deletion of NRG1 interacts with stress to promote neurobehavioral deficits of relevance to schizophrenia. NRG1 heterozygous (HET) mice displayed greater acute stress-induced anxiety-related behavior than wild-type (WT) mice. Repeated stress in adolescence disrupted the normal development of higher prepulse inhibition of startle selectively in NRG1 HET mice but not in WT mice. Further, repeated stress increased dendritic spine density in pyramidal neurons of the medial prefrontal cortex (mPFC) selectively in NRG1 HET mice. Partial genetic deletion of NRG1 also modulated the adaptive response of the hypothalamic-pituitary-adrenal axis to repeated stress, with NRG1 HET displaying a reduced repeated stress-induced level of plasma corticosterone than WT mice. Our results demonstrate that NRG1 confers vulnerability to repeated stress-induced sensorimotor gating deficits, dendritic spine growth in the mPFC, and an abberant endocrine response in adolescence. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 376 | Cereb. Cortex 2014 May 24: 1230-46 |
| PMID | 23283688 |
| Title | Common variants in psychiatric risk genes predict brain structure at birth. |
| Abstract | Studies in adolescents and adults have demonstrated that polymorphisms in putative psychiatric risk genes are associated with differences in brain structure, but cannot address when in development these relationships arise. To determine if common genetic variants in disrupted-in-schizophrenia-1 (DISC1; rs821616 and rs6675281), catechol-O-methyltransferase (COMT; rs4680), neuregulin 1 (NRG1; rs35753505 and rs6994992), apolipoprotein E (APOE; ?3?4 vs. ?3?3), estrogen receptor alpha (ESR1; rs9340799 and rs2234693), brain-derived neurotrophic factor (BDNF; rs6265), and glutamate decarboxylase 1 (GAD1; rs2270335) are associated with individual differences in brain tissue volumes in neonates, we applied both automated region-of-interest volumetry and tensor-based morphometry to a sample of 272 neonates who had received high-resolution magnetic resonance imaging scans. ESR1 (rs9340799) predicted intracranial volume. Local variation in gray matter (GM) volume was significantly associated with polymorphisms in DISC1 (rs821616), COMT, NRG1, APOE, ESR1 (rs9340799), and BDNF. No associations were identified for DISC1 (rs6675281), ESR1 (rs2234693), or GAD1. Of note, neonates homozygous for the DISC1 (rs821616) serine allele exhibited numerous large clusters of reduced GM in the frontal lobes, and neonates homozygous for the COMT valine allele exhibited reduced GM in the temporal cortex and hippocampus, mirroring findings in adults. The results highlight the importance of prenatal brain development in mediating psychiatric risk. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 377 | Biol. Psychiatry 2014 Jul 76: 120-7 |
| PMID | 24210810 |
| Title | Reversible overexpression of bace1-cleaved neuregulin-1 N-terminal fragment induces schizophrenia-like phenotypes in mice. |
| Abstract | Neuregulin-1 (NRG1) is a pleiotropic signaling molecule that regulates neural development, and mutation of NRG1 is a risk factor for schizophrenia. Cleavage of type I ?1 NRG1 isoform by Bace1 releases a secreted N-terminal fragment (NRG1-ntf?), which can bind to a cognate ErbB receptor to activate the specific signaling cascade. This study aimed to determine whether increased expression of NRG1 is beneficial for brain development and functions. We generated transgenic mice overexpressing this fragment under the control of a tetracycline-inducible promoter and examined functional and behavioral changes in mice upon reversible expression of the transgene. Increased expression of full-length NRG1 in mouse neurons has been previously shown to enhance myelination in the central nervous system. Overexpressing NRG1-ntf? enhanced the expression of myelin proteins, consistent with the expected activation of the NRG1 signaling pathway by NRG1-ntf?. Contrary to expectations, overexpressing NRG1-ntf? transgene caused schizophrenia-like behaviors in transgenic mice, and these abnormal behaviors were reversible if the expression of the NRG1-ntf? transgene was turned off. Our molecular assay suggests that protein levels of N-methyl-D-aspartate receptors are reduced in this transgenic mouse model, which might underlie the observed social and cognitive behavioral impairments. Our results indicate that overexpressing the secreted form of NRG1 is sufficient to cause schizophrenia-like behaviors in a mouse model, meaning the effect is independent of the transmembrane and C-terminal domains of NRG1. Hence, genetic gain-of-function mutations of NRG1 are also risk factors for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 378 | Front Behav Neurosci 2014 -1 8: 455 |
| PMID | 25688191 |
| Title | Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia. |
| Abstract | Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1). Recent findings also revealed that NRG1 stimulates the PI3-kinase/AKT signaling pathway, which might be involved in the functional outcomes of some schizophrenic patients. The aim of this study was to evaluate the effect of Akt1-deficiency and NRG1-deficiency alone or in combination in the regulation of behavioral phenotypes, cognition, and social functions using genetically modified mice as a model. Male Akt1 (+/-), NRG1 (+/-), and double mutant mice were bred and compared with their wild-type (WT) littermate controls. In Experiment 1, general physical examination revealed that all mutant mice displayed a normal profile of body weight during development and a normal brain activity with microPET scan. In Experiment 2, no significant genotypic differences were found in our basic behavioral phenotyping, including locomotion, anxiety-like behavior, and sensorimotor gating function. However, both NRG1 (+/-) and double mutant mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In Experiment 3, a synergistic epistasis between Akt1 and NRG1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other 3 groups, especially encountering with a novel male or an ovariectomized female. Double mutant and NRG1 (+/-) mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of Akt1 and NRG1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 379 | Front Behav Neurosci 2014 -1 8: 126 |
| PMID | 24782733 |
| Title | Distinct phenotypes of new transmembrane-domain neuregulin 1 mutant mice and the rescue effects of valproate on the observed schizophrenia-related cognitive deficits. |
| Abstract | Accumulating evidence suggests that neuregulin 1 (NRG1) might be involved in the neurodevelopment, neural plasticity, GABAergic neurotransmission, and pathogenesis of schizophrenia. NRG1 is abundantly expressed in the hippocampus, and emerging studies have begun to reveal the link between NRG1 signaling and cognitive deficits in schizophrenic patients. Because the transmembrane domain of NRG1 is vital for both forward and reverse signaling cascades, new NRG1-deficient mice that carry a truncation of the transmembrane domain of the NRG1 gene were characterized and used in this study to test a NRG1 loss-of-function hypothesis for schizophrenia. Both male and female NRG1 heterozygous mutant mice and their wild-type littermates were used in a series of 4 experiments to characterize the impact of NRG1 on behavioral phenotypes and to determine the importance of NRG1 in the regulation of hippocampal neuromorphology and local GABAergic interneurons. First, a comprehensive battery of behavioral tasks indicated that male NRG1-deficient mice exhibited significant impairments in cognitive functions. Second, pharmacological challenges were conducted and revealed that NRG1 haploinsufficiency altered GABAergic activity in males. Third, although no genotype-specific neuromorphological alterations were found in the hippocampal CA1 pyramidal neurons, significant reductions in the hippocampal expressions of GAD67 and parvalbumin were revealed in the NRG1-deficient males. Fourth, chronic treatment with valproate rescued the observed behavioral deficits and hippocampal GAD67 reduction in NRG1-deficient males. Collectively, these results indicate the potential therapeutic effect of valproate and the importance of NRG1 in the regulation of cognitive functions and hippocampal GABAergic interneurons, especially in males. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 380 | Transl Psychiatry 2014 -1 4: e392 |
| PMID | 24865593 |
| Title | Schizophrenia-risk variant rs6994992 in the neuregulin-1 gene on brain developmental trajectories in typically developing children. |
| Abstract | The neuregulin-1 (NRG1) gene is one of the best-validated risk genes for schizophrenia, and psychotic and bipolar disorders. The rs6994992 variant in the NRG1 promoter (SNP8NRG243177) is associated with altered frontal and temporal brain macrostructures and/or altered white matter density and integrity in schizophrenic adults, as well as healthy adults and neonates. However, the ages when these changes begin and whether neuroimaging phenotypes are associated with cognitive performance are not fully understood. Therefore, we investigated the association of the rs6994992 variant on developmental trajectories of brain macro- and microstructures, and their relationship with cognitive performance. A total of 972 healthy children aged 3-20 years had the genotype available for the NRG1-rs6994992 variant, and were evaluated with magnetic resonance imaging (MRI) and neuropsychological tests. Age-by-NRG1-rs6994992 interactions and genotype effects were assessed using a general additive model regression methodology, covaried for scanner type, socioeconomic status, sex and genetic ancestry factors. Compared with the C-carriers, children with the TT-risk-alleles had subtle microscopic and macroscopic changes in brain development that emerge or reverse during adolescence, a period when many psychiatric disorders are manifested. TT-children at late adolescence showed a lower age-dependent forniceal volume and lower fractional anisotropy; however, both measures were associated with better episodic memory performance. To our knowledge, we provide the first multimodal imaging evidence that genetic variation in NRG1 is associated with age-related changes on brain development during typical childhood and adolescence, and delineated the altered patterns of development in multiple brain regions in children with the T-risk allele(s). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 381 | JAMA Psychiatry 2014 May 71: 531-9 |
| PMID | 24622944 |
| Title | Striatal response to reward anticipation: evidence for a systems-level intermediate phenotype for schizophrenia. |
| Abstract | Attenuated ventral striatal response during reward anticipation is a core feature of schizophrenia that is seen in prodromal, drug-naive, and chronic schizophrenic patients. schizophrenia is highly heritable, raising the possibility that this phenotype is related to the genetic risk for the disorder. To examine a large sample of healthy first-degree relatives of schizophrenic patients and compare their neural responses to reward anticipation with those of carefully matched controls without a family psychiatric history. To further support the utility of this phenotype, we studied its test-retest reliability, its potential brain structural contributions, and the effects of a protective missense variant in neuregulin 1 (NRG1) linked to schizophrenia by meta-analysis (ie, rs10503929). Examination of a well-established monetary reward anticipation paradigm during functional magnetic resonance imaging at a university hospital; voxel-based morphometry; test-retest reliability analysis of striatal activations in an independent sample of 25 healthy participants scanned twice with the same task; and imaging genetics analysis of the control group. A total of 54 healthy first-degree relatives of schizophrenic patients and 80 controls matched for demographic, psychological, clinical, and task performance characteristics were studied. Blood oxygen level-dependent response during reward anticipation, analysis of intraclass correlations of functional contrasts, and associations between striatal gray matter volume and NRG1 genotype. Compared with controls, healthy first-degree relatives showed a highly significant decrease in ventral striatal activation during reward anticipation (familywise error-corrected P?.05), and affected by the NRG1 genotype (higher striatal responses in controls with the protective rs10503929 C allele; familywise error-corrected P?Healthy first-degree relatives of schizophrenic patients show altered striatal activation during reward anticipation in a directionality and localization consistent with prior patient findings. This provides evidence for a functional neural system mechanism related to familial risk. The phenotype can be assessed reliably, is independent of alterations in striatal structure, and is influenced by a schizophrenia candidate gene variant in NRG1. These data encourage us to further investigate the genetic and molecular contributions to this phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 382 | J. Mol. Neurosci. 2015 May 56: 205-11 |
| PMID | 25529856 |
| Title | Genetic variability testing of neurodevelopmental genes in schizophrenic patients. |
| Abstract | This study investigated the associations between single nucleotide polymorphisms in the neurodevelopmental Disrupted In schizophrenia 1 (DISC1 ), neuregulin 1 (NRG1), brain-derived neurotrophic factor (BDNF) and NOTCH4 genes and the clinical symptoms and the occurrence of treatment-resistant schizophrenia in the Slovenian population. We included 138 schizophrenia patients, divided into treatment-responsive and treatment-resistant group and 94 healthy blood donors. All subjects were genotyped for eight polymorphisms (DISC1 rs6675281, DISC1 rs821616, NRG1 rs3735781, NRG1 rs3735782, NRG1 rs10503929, NRG1 rs3924999, BDNF rs6265, NOTCH rs367398) and investigated for associations with clinical variables. NOTCH4 rs367398 AA/AG was significantly associated with worse Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) score. NOTCH4 rs367398 was not statistically significantly associated with the occurrence of treatment-resistant schizophrenia after the correction for multiple testing. Our data indicate that NOTCH4 polymorphism can influence clinical symptoms in Slovenian patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 383 | Mol. Psychiatry 2015 May 20: 555-62 |
| PMID | 25754081 |
| Title | Evaluating historical candidate genes for schizophrenia. |
| Abstract | Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 384 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2015 Jan 56: 149-54 |
| PMID | 25194460 |
| Title | Perinatal asphyxia alters neuregulin-1 and COMT gene expression in the medial prefrontal cortex in rats. |
| Abstract | Epidemiological studies suggest that perinatal complications, particularly hypoxia-related ones, increase the risk of schizophrenia. Recent genetic studies of the disorder have identified several putative susceptibility genes, some of which are known to be regulated by hypoxia. It can be postulated therefore that birth complications that cause hypoxia in the fetal brain may be associated with a dysregulation in the expression of some of the schizophrenia candidate genes. To test this, we used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Caesarean section birth, and examined the expression of mRNA of five of the putative susceptibility genes (NRG1, ErbB4, AKT1, COMT and BDNF) by real-time quantitative PCR in the medial prefrontal cortex (mPFC) and the hippocampus at 6 and 12 weeks after birth. The expression of NRG1 mRNA was significantly decreased in the mPFC, but not in the hippocampus, at 6 and 12 weeks after birth. In addition, a significant increase in COMT mRNA expression was observed in the mPFC at 12 weeks. The alteration in mRNA levels of NRG1 and COMT was not associated with a change in their protein levels. These results suggest that perinatal asphyxia may lead to disturbances in the PFC, which in turn may exert a long-lasting influence on the expression of specific genes, such as NRG1 and COMT. Our results also suggest that translational interruption may occur in this model of perinatal asphyxia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 385 | Nat Commun 2015 -1 6: 10118 |
| PMID | 26656849 |
| Title | Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex. |
| Abstract | Neuregulin-1 (NRG1) and its receptor ErbB4 influence several processes of neurodevelopment, but the mechanisms regulating this signalling in the mature brain are not well known. DISC1 is a multifunctional scaffold protein that mediates many cellular processes. Here we present a functional relationship between DISC1 and NRG1-ErbB4 signalling in mature cortical interneurons. By cell type-specific gene modulation in vitro and in vivo including in a mutant DISC1 mouse model, we demonstrate that DISC1 inhibits NRG1-induced ErbB4 activation and signalling. This effect is likely mediated by competitive inhibition of binding of ErbB4 to PSD95. Finally, we show that interneuronal DISC1 affects NRG1-ErbB4-mediated phenotypes in the fast spiking interneuron-pyramidal neuron circuit. Post-mortem brain analyses and some genetic studies have reported interneuronal deficits and involvement of the DISC1, NRG1 and ErbB4 genes in schizophrenia, respectively. Our results suggest a mechanism by which cross-talk between DISC1 and NRG1-ErbB4 signalling may contribute to these deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 386 | Int. Rev. Neurobiol. 2015 -1 124: 113-31 |
| PMID | 26472527 |
| Title | Role of the Neuregulin Signaling Pathway in Nicotine Dependence and Co-morbid Disorders. |
| Abstract | Smoking is currently the leading cause of preventable death in the United States and is responsible for over four million deaths annually worldwide. Therefore, there is a vast clinical unmet need with regards to therapeutics targeting smoking cessation. This is even more apparent when examining smokers co-morbid with psychiatric illness, as rates of smoking in this population are ~4× higher than in the general population. Examining common genetic and molecular signaling pathways impinging upon both smoking behavior and psychiatric illness will lead to a better understanding of co-morbid disorders and potential development of novel therapeutics. Studies have implicated the Neuregulin Signaling Pathway in the pathophysiology of a number of psychiatric illnesses. Additionally, recent studies have also shown an association between the Neuregulin Signaling Pathway and smoking behaviors. This review outlines basic mechanisms of the Neuregulin Signaling Pathway and how it may be exploited for precision medicine approaches in treating nicotine dependence and mental illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 387 | J. Biol. Chem. 2015 Aug 290: 20233-44 |
| PMID | 26092725 |
| Title | Neuregulin 1 Controls Glutamate Uptake by Up-regulating Excitatory Amino Acid Carrier 1 (EAAC1). |
| Abstract | Neuregulin 1 (NRG1) is a trophic factor that is thought to have important roles in the regulating brain circuitry. Recent studies suggest that NRG1 regulates synaptic transmission, although the precise mechanisms remain unknown. Here we report that NRG1 influences glutamate uptake by increasing the protein level of excitatory amino acid carrier (EAAC1). Our data indicate that NRG1 induced the up-regulation of EAAC1 in primary cortical neurons with an increase in glutamate uptake. These in vitro results were corroborated in the prefrontal cortex (PFC) of mice given NRG1. The stimulatory effect of NRG1 was blocked by inhibition of the NRG1 receptor ErbB4. The suppressed expression of ErbB4 by siRNA led to a decrease in the expression of EAAC1. In addition, the ablation of ErbB4 in parvalbumin (PV)-positive neurons in PV-ErbB4(-/-) mice suppressed EAAC1 expression. Taken together, our results show that NRG1 signaling through ErbB4 modulates EAAC1. These findings link proposed effectors in schizophrenia: NRG1/ErbB4 signaling perturbation, EAAC1 deficit, and neurotransmission dysfunction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 388 | Neuropsychopharmacology 2015 Mar 40: 974-86 |
| PMID | 25308353 |
| Title | Amygdala NRG1-ErbB4 is critical for the modulation of anxiety-like behaviors. |
| Abstract | Anxiety disorder is related to the pathophysiology of psychiatric diseases, including major depression, substance abuse, and schizophrenia. The amygdala is important for manifestation and modulation of anxiety. However, relatively little is known regarding the mechanisms that control the amygdala inhibitory activity that is involved in anxiety. We found that almost all ErbB4, which is the only autonomous receptor of neuregulin 1 (NRG1) in the basolateral amygdala (BLA), was expressed in GABAergic neurons. Endogenous NRG1-ErbB4 signaling pathway in the BLA could modulate anxiety-like behaviors and GABA release, whereas it had no effect on glutamatergic transmission. The administration of NRG1 into the BLA of high-anxiety mice alleviated their anxiety and enhanced GABAergic neurotransmission. Moreover, exogenous NRG1 also produced an anxiolytic effect in the stressed mice. Together, these observations indicated that NRG1-ErbB4 signaling is critical to maintaining GABAergic activity in the amygdala and thus to modulating anxiety-like behaviors. Because NRG1 and ErbB4 are susceptibility genes of schizophrenia, our findings might also help to explain the potential mechanism of emotional abnormality in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 389 | Mol. Psychiatry 2015 Aug 20: 959-73 |
| PMID | 25266126 |
| Title | Neuregulin 1 signalling modulates mGluR1 function in mesencephalic dopaminergic neurons. |
| Abstract | Neuregulin 1 (NRG1) is a trophic factor that has an essential role in the nervous system by modulating neurodevelopment, neurotransmission and synaptic plasticity. Despite the evidence that NRG1 and its receptors, ErbB tyrosine kinases, are expressed in mesencephalic dopaminergic nuclei and their functional alterations are reported in schizophrenia and Parkinson's disease, the role of NRG1/ErbB signalling in dopaminergic neurons remains unclear. Here we found that NRG1 selectively increases the metabotropic glutamate receptor 1 (mGluR1)-activated currents by inducing synthesis and trafficking to membrane of functional receptors and stimulates phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway, which is required for mGluR1 function. Notably, an endogenous NRG1/ErbB tone is necessary to maintain mGluR1 function, by preserving its surface membrane expression in dopaminergic neurons. Consequently, it enables striatal mGluR1-induced dopamine outflow in in vivo conditions. Our results identify a novel role of NRG1 in the dopaminergic neurons, whose functional alteration might contribute to devastating diseases, such as schizophrenia and Parkinson's disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 390 | Schizophr. Res. 2015 Mar 162: 112-7 |
| PMID | 25579050 |
| Title | Evidence for schizophrenia susceptibility alleles in the Indian population: An association of neurodevelopmental genes in case-control and familial samples. |
| Abstract | schizophrenia is a severe psychiatric disorder with lifetime prevalence of ~1% worldwide. A genotyping study was conducted using a custom panel of Illumina 1536 SNPs in 840 schizophrenia cases and 876 controls (351 patients and 385 controls from North India; and 436 patients, 401 controls and 143 familial samples with 53 probands containing 37 complete and 16 incomplete trios from South India). Meta-analysis of this population of Indo-European and Dravidian ancestry identified three strongly associated variants with schizophrenia: STT3A (rs548181, p=1.47×10(-5)), NRG1 (rs17603876, p=8.66×10(-5)) and GRM7 (rs3864075, p=4.06×10(-3)). Finally, a meta-analysis was conducted comparing our data with data from the schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ) that supported rs548181 (p=1.39×10(-7)). In addition, combined analysis of sporadic case-control association and a transmission disequilibrium test in familial samples from South Indian population identified three associations: rs1062613 (p=3.12×10(-3)), a functional promoter variant of HTR3A; rs6710782 (p=3.50×10(-3)), an intronic variant of ERBB4; and rs891903 (p=1.05×10(-2)), an intronic variant of EBF1. The results support the risk variants observed in the earlier published work and suggest a potential role of neurodevelopmental genes in the schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 391 | Brain Struct Funct 2015 Dec -1: -1 |
| PMID | 26721794 |
| Title | Altered resonance properties of somatosensory responses in mice deficient for the schizophrenia risk gene Neuregulin 1. |
| Abstract | To reveal the neuronal underpinnings of sensory processing deficits in patients with schizophrenia, previous studies have investigated brain activity in response to sustained sensory stimulation at various frequencies. This paradigm evoked neural activity at the stimulation frequency and harmonics thereof. During visual and auditory stimulation that elicited enhanced or 'resonant' responses in healthy controls, patients with schizophrenia displayed reduced activity. The present study sought to elucidate the cellular basis of disease-related deficits in sensory resonance properties using mice heterozygous for the schizophrenia susceptibility gene Neuregulin 1 (NRG1). We applied repetitive whisker stimulation at 1-15 Hz, a range relevant to whisking behavior in mice, and measured cellular activity in the primary somatosensory cortex. At frequencies where control mice displayed enhancements in measures of response magnitude and precision, NRG1 (+/-) mutants showed reductions. Our results demonstrate for the first time a link between a mutation of a schizophrenia risk gene and altered neuronal resonance properties in sensory cortex. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 392 | PLoS ONE 2015 -1 10: e0124114 |
| PMID | 25992564 |
| Title | Neuregulin 1 expression and electrophysiological abnormalities in the Neuregulin 1 transmembrane domain heterozygous mutant mouse. |
| Abstract | The Neuregulin 1 transmembrane domain heterozygous mutant (NRG1 TM HET) mouse is used to investigate the role of NRG1 in brain function and schizophrenia-like behavioural phenotypes. However, the molecular alterations in brain NRG1 expression that underpin the behavioural observations have been assumed, but not directly determined. Here we comprehensively characterise mRNA NRG1 transcripts throughout development of the NRG1 TM HET mouse. In addition, we investigate the regulation of high-frequency (gamma) electrophysiological oscillations in this mutant mouse to associate molecular changes in NRG1 with a schizophrenia-relevant neurophysiological profile. Using exonic probes spanning the cysteine-rich, epidermal growth factor (EGF)-like, transmembrane and intracellular domain encoding regions of NRG1, mRNA levels were measured using qPCR in hippocampus and frontal cortex from male and female NRG1 TM HET and wild type-like (WT) mice throughout development. We also performed electrophysiological recordings in adult mice and analysed gamma oscillatory at baseline, in responses to auditory stimuli and to ketamine. In both hippocampus and cortex, NRG1 TM HET mice show significantly reduced expression of the exon encoding the transmembrane domain of NRG1 compared with WT, but unaltered mRNA expression encoding the extracellular bioactive EGF-like and the cysteine-rich (type III) domains, and development-specific and region-specific reductions in the mRNA encoding the intracellular domain. Hippocampal NRG1 protein expression was not altered, but NMDA receptor NR2B subunit phosphorylation was lower in NRG1 TM HET mice. We identified elevated ongoing and reduced sensory-evoked gamma power in NRG1 TM HET mice. We found no evidence to support the claim that the NRG1 TM HET mouse represents a simple haploinsufficient model. Further research is required to explore the possibility that mutation results in a gain of NRG1 function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 393 | Curr. Mol. Med. 2015 -1 15: 222-36 |
| PMID | 25817857 |
| Title | Neurobehavioral Differences Between Mice Receiving Distinct Neuregulin Variants as Neonates; Impact on Sensitivity to MK-801. |
| Abstract | Neuregulin-1 (NRG1) is a well-recognized risk gene for schizophrenia and is often implicated in the neurodevelopmental hypothesis of this illness. Alternative splicing and proteolytic processing of the NRG1 gene produce more than 30 structural variants; however, the neuropathological roles of individual variants remain to be characterized. On the basis of the neurodevelopmental hypothesis of schizophrenia, we administered eNRG1 (0.1~1.0 ?g/g), a core epidermal growth factor-like (EGF) domain common for all splicing NRG1 variants, to neonatal mice and compared their behavioral performance with mice challenged with a full mature form of type 1 NRG1 variant. During the neonatal stage, recombinant eNRG1 protein administrated from the periphery passed the blood-brain barrier and activated its receptor (ErbB4) in the brain. In adults, the mice receiving the highest dose exhibited lower locomotor activity and deficits in prepulse inhibition and tonedependent fear learning, although the hearing reduction of the eNRG1-treated mice may explain these behavioral deficits. Neonatal eNRG1 treatment also significantly potentiated MK-801-driven locomotor activity in an eNRG1 dose-dependent manner. In parallel eNRG1 treatment enhanced MK-801-driven c-Fos induction and decreased immunoreactivity for NMDA receptor subunits in adult brain. In contrast, mice that had been treated with the same molar dose of a full mature form of type 1 NRG1 as neonates did not exhibit hypersensitivity to MK-801. However, both animal models exhibited similar hypersensitivity to methamphetamine. Collectively, our findings suggest that aberrant peripheral NRG1 signals during neurodevelopment alter later behavioral traits and auditory functions in the NRG1 subtype-dependent manner. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 394 | Psychiatry Res 2015 Jun 227: 366-8 |
| PMID | 25858800 |
| Title | Genetic association analyses of neuregulin 1 gene polymorphism with endopheontype for sociality of Korean autism spectrum disorders family. |
| Abstract | To determine the genetic association between qualitative and quantitative traits of autism spectrum disorder (ASD) and neuregulin 1 (NRG1)-a schizophrenia candidate gene-we examined six single nucleotide polymorphisms (SNPs) in NRG1 using a family-based association test (FBAT) in Korean families with ASD. rs35753505 and rs6994992 SNPs in NRG1 revealed a statistically significant family-based association with three quantitative traits for sociality. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 395 | Front Cell Neurosci 2015 -1 9: 472 |
| PMID | 26733804 |
| Title | ErbB4 in Laminated Brain Structures: A Neurodevelopmental Approach to Schizophrenia. |
| Abstract | The susceptibility genes for schizophrenia Neuregulin-1 (NRG1) and ErbB4 have critical functions during brain development and in the adult. Alterations in the ErbB4 signaling pathway cause a variety of neurodevelopmental defects including deficiencies in neuronal migration, synaptic plasticity, and myelination. I have used the ErbB4(-/-) HER4(heart) KO mice to study the neurodevelopmental insults associated to deficiencies in the NRG1-ErbB4 signaling pathway and their potential implication with brain disorders such as schizophrenia, a chronic psychiatric disease affecting 1% of the population worldwide. ErbB4 deletion results in an array of neurodevelopmental deficits that are consistent with a schizophrenic model. First, similar defects appear in multiple brain structures, from the cortex to the cerebellum. Second, these defects affect multiple aspects of brain development, from deficits in neuronal migration to impairments in excitatory/inhibitory systems, including reductions in brain volume, cortical and cerebellar heterotopias, alterations in number and distribution of specific subpopulations of interneurons, deficiencies in the astrocytic and oligodendrocytic lineages, and additional insults in major brain structures. This suggests that alterations in specific neurodevelopmental genes that play similar functions in multiple neuroanatomical structures might account for some of the symptomatology observed in schizophrenic patients, such as defects in cognition. ErbB4 mutation uncovers flaws in brain development that are compatible with a neurodevelopmental model of schizophrenia, and it establishes a comprehensive model to study the basis of the disorder before symptoms are detected in the adult. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 396 | Brain Imaging Behav 2015 Mar 9: 128-40 |
| PMID | 25744101 |
| Title | ERBB4 polymorphism and family history of psychiatric disorders on age-related cortical changes in healthy children. |
| Abstract | Genetic variations in ERBB4 were associated with increased susceptibility for schizophrenia (SCZ) and bipolar disorders (BPD). Structural imaging studies showed cortical abnormalities in adolescents and adults with SCZ or BPD. However, less is known about subclinical cortical changes or the influence of ERBB4 on cortical development. 971 healthy children (ages 3-20 years old; 462 girls and 509 boys) were genotyped for the ERBB4-rs7598440 variants, had structural MRI, and cognitive evaluation (NIH Toolbox ®). We investigated the effects of ERBB4 variants and family history of SCZ and/or BPD (FH) on cortical measures and cognitive performances across ages 3-20 years using a general additive model. Variations in ERBB4 and FH impact differentially the age-related cortical changes in regions often affected by SCZ and BPD. The ERBB4-TT-risk genotype children with no FH had subtle cortical changes across the age span, primarily located in the left temporal lobe and superior parietal cortex. In contrast, the TT-risk genotype children with FH had more pronounced age-related changes, mainly in the frontal lobes compared to the non-risk genotype children. Interactive effects of age, FH and ERBB4 variations were also found on episodic memory and working memory, which are often impaired in SCZ and BPD. Healthy children carrying the risk-genotype in ERBB4 and/or with FH had cortical measures resembling those reported in SCZ or BPD. These subclinical cortical variations may provide early indicators for increased risk of psychiatric disorders and improve our understanding of the effect of the NRG1-ERBB4 pathway on brain development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 397 | Pharmacogenet. Genomics 2015 Apr 25: 173-85 |
| PMID | 25714000 |
| Title | Large-scale candidate gene study to identify genetic risk factors predictive of paliperidone treatment response in patients with schizophrenia. |
| Abstract | Clinical response to antipsychotic medications can vary markedly in patients with schizophrenia. Identifying genetic variants associated with treatment response could help optimize patient care and outcome. To this end, we carried out a large-scale candidate gene study to identify genetic risk factors predictive of paliperidone efficacy. A central nervous system custom chip containing single nucleotide polymorphisms from 1204 candidate genes was utilized to genotype a discovery cohort of 684 schizophrenia patients from four clinical studies of paliperidone extended-release and paliperidone palmitate. Variants predictive of paliperidone efficacy were identified and further tested in four independent replication cohorts of schizophrenic patients (N=2856). We identified an SNP in ERBB4 that may contribute toward differential treatment response to paliperidone. The association trended in the same direction as the discovery cohort in two of the four replication cohorts, but ultimately did not survive multiple testing corrections. The association was not replicated in the other two independent cohorts. We also report several SNPs in well-known schizophrenia candidate genes that show suggestive associations with paliperidone efficacy. These preliminary findings suggest that genetic variation in the ERBB4 gene may differentially affect treatment response to paliperidone in individuals with schizophrenia. They implicate the neuregulin 1 (NRG1)-ErbB4 pathway for modulating antipsychotic response. However, these findings were not robustly reproduced in replication cohorts. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 398 | Psychiatry Res 2015 Feb 225: 347-54 |
| PMID | 25576368 |
| Title | Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain. |
| Abstract | Neuregulin-1 (NRG1) and ErbB4 genes have been identified as candidate genes for schizophrenia. Post-mortem studies indicated that NRG1-ErbB4 signalling is impaired in schizophrenia subjects. This study investigated whether short- or long-term antipsychotic treatment has different effects on the expression of NRG1 and ErbB4 receptors. Female Sprague-Dawley rats were treated orally with either aripiprazole (0.75 mg/kg), haloperidol (0.1 mg/kg), olanzapine (0.5 mg/kg), or vehicle, 3 times/day for 1 or 12 weeks. Western blotting was performed to examine the expression of NRG1 isoforms (135 kDa, 70 kDa and 40 kDa) and ErbB4 receptors. Both 1-week haloperidol and olanzapine treatment increased NRG1-70kDa expression in the hippocampus; haloperidol also up-regulated ErbB4 levels in the prefrontal cortex (PFC). In the 12-week group, aripiprazole decreased the expression of all three NRG1 isoforms and ErbB4 receptors in the PFC, NRG1-70 kDa and -40 kDa in the cingulate cortex (Cg), and NRG1-135 kDa, -70 kDa and ErbB4 receptors in the hippocampus; haloperidol reduced NRG1-135 kDa in the PFC, NRG1-40 kDa in all three brain regions, and ErbB4 receptor levels in the PFC and hippocampus; NRG1-40 kDa in the PFC and Cg was also down-regulated by olanzapine. These results suggest that the time-dependent and region-specific effects of antipsychotics on NRG1-ErbB4 signalling may contribute to the efficacy of antipsychotics to treat schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 399 | Mol. Psychiatry 2015 Oct 20: 1251-60 |
| PMID | 25349163 |
| Title | Calcyon stimulates neuregulin 1 maturation and signaling. |
| Abstract | Neuregulin1 (NRG1) is a single transmembrane protein that plays a critical role in neural development and synaptic plasticity. Both NRG1 and its receptor, ErbB4, are well-established risk genes of schizophrenia. The NRG1 ecto-domain (ED) binds and activates ErbB4 following proteolytic cleavage of pro-NRG1 precursor protein. Although several studies have addressed the function of NRG1 in brain, very little is known about the cleavage and shedding mechanism. Here we show that the neuronal vesicular protein calcyon is a potent activator and key determinant of NRG1 ED cleavage and shedding. Calcyon stimulates clathrin-mediated endocytosis and endosomal targeting; and its levels are elevated in postmortem brains of schizophrenics. Overexpression of calcyon stimulates NRG1 cleavage and signaling in vivo, and as a result, GABA transmission is enhanced in calcyon overexpressing mice. Conversely, NRG1 cleavage, ErbB4 activity and GABA transmission are decreased in calcyon null mice. Moreover, stimulation of NRG1 cleavage by calcyon was recapitulated in HEK 293 cells suggesting the mechanism involved is cell-autonomous. Finally, studies with site-specific mutants in calcyon and inhibitors for the major sheddases indicate that the stimulatory effects of calcyon on NRG1 cleavage and shedding depend on clathrin-mediated endocytosis, ?-secretase 1, and interaction with clathrin adaptor proteins. Together these results identify a novel mechanism for NRG1 cleavage and shedding. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 400 | Schizophr Res Cogn 2015 Jun 2: 56-63 |
| PMID | 26346124 |
| Title | Hierarchical Classes Analysis (HICLAS): A novel data reduction method to examine associations between biallelic SNPs and perceptual organization phenotypes in schizophrenia. |
| Abstract | The power of SNP association studies to detect valid relationships with clinical phenotypes in schizophrenia is largely limited by the number of SNPs selected and non-specificity of phenotypes. To address this, we first assessed performance on two visual perceptual organization tasks designed to avoid many generalized deficit confounds, Kanizsa shape perception and contour integration, in a schizophrenia patient sample. Then, to reduce the total number of candidate SNPs analyzed in association with perceptual organization phenotypes, we employed a two-stage strategy: first a priori SNPs from three candidate genes were selected (GAD1, NRG1 and DTNBP1); then a Hierarchical Classes Analysis (HICLAS) was performed to reduce the total number of SNPs, based on statistically related SNP clusters. HICLAS reduced the total number of candidate SNPs for subsequent phenotype association analyses from 6 to 3. MANCOVAs indicated that rs10503929 and rs1978340 were associated with the Kanizsa shape perception filling in metric but not the global shape detection metric. rs10503929 was also associated with altered contour integration performance. SNPs not selected by the HICLAS model were unrelated to perceptual phenotype indices. While the contribution of candidate SNPs to perceptual impairments requires further clarification, this study reports the first application of HICLAS as a hypothesis-independent mathematical method for SNP data reduction. HICLAS may be useful for future larger scale genotype-phenotype association studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 401 | Bipolar Disord 2015 Dec 17: 859-68 |
| PMID | 26534905 |
| Title | Polymorphisms of dopamine pathway genes NRG1 and LMX1A are associated with cognitive performance in bipolar disorder. |
| Abstract | LIM homeobox transcription factor 1, alpha (LMX1A) and neuregulin 1 (NRG1) are susceptibility genes for schizophrenia that have been implicated in the dopaminergic pathway and have been associated with altered cognitive functioning. We hypothesized that single nucleotide polymorphisms (SNPs) in LMX1A and NRG1 would be associated with cognitive functioning in bipolar disorder. In total, four SNPs were directly genotyped. Regression models with five aggregated cognitive domains and intelligence quotient (IQ) score were run using risk variants of LMX1A (rs11809911, rs4657412, rs6668493) and NRG1 (rs35753505) as predictors. Models were performed in a clinical sample of patients with bipolar disorder (n = 114) and healthy controls (n = 104). The risk variants of the rs11809911 SNP in LMX1A were negatively associated with IQ score and memory/learning, whereas the risk variants of rs35753505 in NRG1 were positively associated with IQ score (adjusted R(2) = 0.17, Q = 0.006) and memory/learning (adjusted R(2) = 0.24, Q = 0.001). The risk variants of the rs35753505 SNP in NRG1 were positively associated with language (adjusted R(2) = 0.11, Q = 0.006), visuospatial functions (adjusted R(2) = 0.23, Q = 0.001), and attention/speed (adjusted R(2) = 0.25, Q = 0.001). Results could not be replicated in controls. The risk variants of the rs35753505 SNP were associated with increased performance in several cognitive domains and IQ, whereas the risk variants of the rs11809911 SNP in LMX1A was associated with reduced IQ and memory/learning. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 402 | Int. J. Neuropsychopharmacol. 2015 May 18: pyu114 |
| PMID | 26478928 |
| Title | Neuregulin 1 Prevents Phencyclidine-Induced Behavioral Impairments and Disruptions to GABAergic Signaling in Mice. |
| Abstract | Substantial evidence from human post-mortem and genetic studies has linked the neurotrophic factor neuregulin 1 (NRG1) to the pathophysiology of schizophrenia. Genetic animal models and in vitro experiments have suggested that altered NRG1 signaling, rather than protein changes, contributes to the symptomatology of schizophrenia. However, little is known about the effect of NRG1 on schizophrenia-relevant behavior and neurotransmission (particularly GABAergic and glutamatergic) in adult animals. To address this question, we treated adult mice with the extracellular signaling domain of NRG1 and assessed spontaneous locomotor activity and acoustic startle response, as well as extracellular GABA, glutamate, and glycine levels in the prefrontal cortex and hippocampus via microdialysis. Furthermore, we asked whether the effect of NRG1 would differ under schizophrenia-relevant impairments in mice and therefore co-treated mice with NRG1 and phencyclidine (PCP) (3 mg/kg). Acute intraventricularly- or systemically-injected NRG1 did not affect spontaneous behavior, but prevented PCP induced hyperlocomotion and deficits of prepulse inhibition. NRG1 retrodialysis (10 nM) reduced extracellular glutamate and glycine levels in the prefrontal cortex and hippocampus, and prevented PCP-induced increase in extracellular GABA levels in the hippocampus. With these results, we provide the first compelling in vivo evidence for the involvement of NRG1 signaling in schizophrenia-relevant behavior and neurotransmission in the adult nervous system, which highlight its treatment potential. Furthermore, the ability of NRG1 treatment to alter GABA, glutamate, and glycine levels in the presence of PCP also suggests that NRG1 signaling has the potential to alter disrupted neurotransmission in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 403 | Neurosci. Lett. 2015 Oct 606: 220-4 |
| PMID | 26365407 |
| Title | Decreased plasma levels of neureglin-1 in drug naïve patients and chronic patients with schizophrenia. |
| Abstract | Although the neuregulin-1 (NRG1) gene is one of the susceptibility genes for schizophrenia and various other psychiatric diseases, it remains unclear how individual psychiatric diseases affect the expression of the NRG1 protein in patients. A previous study reported a schizophrenia-linked decrease in serum NRG1 levels. The present study aimed to replicate this initial finding and to assess its disease specificity for schizophrenia. We collected plasma samples from drug-naïve patients with first-episode schizophrenia (n=80), patients with chronic schizophrenia (n=86), patients with bipolar I disorder (n=60), patients with bipolar II disorder (n=60) and patients with major depressive disorder (n=60), we measured the plasma levels of NRG1?1 and compared the levels with those of age- and sex-matched healthy volunteers (n=82). One-way ANOVA and post hoc analyses detected specific NRG1?1 decreases in the participants with first-episode and chronic schizophrenia but not in those with bipolar I disorder, bipolar II disorder or major depressive disorder. The mean plasma levels of NRG1?1 immunoreactivity were 4.27±0.71 ng/mL in the participants with first-episode schizophrenia, 4.08±0.64 ng/mL in the participants with chronic schizophrenia and 7.21±0.91 ng/mL in the healthy controls. Although we analyzed the pathological correlations of NRG1?1 immunoreactivity in terms of the clinical parameters of the sample, we observed only weak positive correlations with the age of the participants with chronic schizophrenia and the disease onset times of the participants with bipolar II disorder. We failed to identify correlations between other clinical parameters and plasma NRG1?1 immunoreactivity among all patient subjects. These findings suggest that NRG1 may serve as a relatively specific disease marker for schizophrenia. However, the pathological role of this decrease must be explored further. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 404 | Psychiatr. Genet. 2015 Aug 25: 147-54 |
| PMID | 25967537 |
| Title | Effects of genetic variations in NRG1 on cognitive domains in patients with schizophrenia and healthy individuals. |
| Abstract | The neuregulin 1 (NRG1) gene has been investigated as a candidate susceptibility gene for schizophrenia. A number of studies have also explored the genetic effect of NRG1 on cognitive deficits related to schizophrenia, and thus far generated inconsistent results. The current study aimed to determine whether genetic variations in NRG1 are associated with cognitive domains in schizophrenic patients and healthy individuals. Comprehensive neuropsychological tests composed of six cognitive domains were administered to 135 clinically stable patients with schizophrenia and 119 healthy individuals. On the basis of previous reports of positive association, a total of four single nucleotide polymorphisms were analyzed. In testing the genotype effect on cognitive domains, we used repeated-measure analysis for six cognitive domain scores of each individual as repeated measurements. An association of P-value less than 0.05 with at least one cognitive domain in patients and/or healthy individuals was observed for all of the single nucleotide polymorphisms. After applying the correction for multiple testing, the association remained statistically significant between rs6994992 and general cognitive ability (g) in the patient group and between rs2439272 and the 'working memory' domain in the group of healthy participants. This study suggests the involvement of NRG1 in the susceptibility for developing cognitive deficits in schizophrenic patients. For some cognitive domains, its genetic effect was also significant in generating interindividual variability within the normal functional range. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 405 | Transl Psychiatry 2015 -1 5: e553 |
| PMID | 25897834 |
| Title | The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response. |
| Abstract | Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P=5.03E-08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P=1.20E-06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 406 | Neuropsychobiology 2015 Apr 71: 103-111 |
| PMID | 25871612 |
| Title | Progressive Structural Brain Changes and NRG1 Gene Variants in First-Episode Nonaffective Psychosis. |
| Abstract | Structural brain abnormalities are already present during the early phases of psychosis, but factors underlying brain volume changes are still not well understood. The neuregulin 1 gene (NRG1), influencing neurodevelopment and neuroplasticity, has been associated with schizophrenia. Our aim was to examine whether variations in the NRG1 gene (SNP8NRG221132, SNP8NRG6221533 and SNP8NRG243177 polymorphisms) influence longitudinal changes in the brain during a first episode of psychosis (FEP). A 3-year follow-up magnetic resonance imaging (MRI) study was performed. Fifty-nine minimally medicated patients who were experiencing FEP and 14 healthy control individuals underwent genotyping and structural brain MRI at baseline and at 1- and 3-year follow-up. A comparison of brain volumes, gray matter, white matter (WM), lateral ventricles (LV), cortical cerebrospinal fluid, and thalamus and caudate was made between the groups according to their genotype. In patients, the SNP8NRG6221533 risk C allele was significantly associated with increased LV volume across time. C allele carriers had significantly less WM compared with subjects homozygous for the T allele after the follow-up. No other significant differences were observed among subgroups. No significant changes according to the genotypes were found in healthy individuals. Our findings suggest that variations of neurodevelopment-related genes, such as the NRG1 gene, can contribute to brain abnormalities described in early phases of schizophrenia and progressive changes during the initial years of the illness. To our knowledge, it is the first time that a relation between NRG1 polymorphisms and longitudinal brain changes is reported. © 2015 S. Karger AG, Basel. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 407 | Meth. Enzymol. 2015 -1 552: 325-49 |
| PMID | 25707284 |
| Title | Sleep and circadian rhythm disruption and recognition memory in schizophrenia. |
| Abstract | schizophrenia patients often show irregularities in sleep and circadian rhythms and deficits in recognition memory. Similar phenotypes are seen in schizophrenia-relevant genetic mouse models, such as synaptosomal associated protein of 25 kDa (Snap-25) point mutant mice, vasoactive intestinal peptide receptor 2 (Vipr2) knockout mice, and neuregulin 1 (NRG1)-deficient mice. Sleep and circadian abnormalities and impaired recognition memory may be causally related in both schizophrenia patients and schizophrenia-relevant mouse models, since sleep deprivation, abnormal photic input, and the manipulation of core clock genes (cryptochrome 1/2) can all disrupt object recognition memory in rodent models. The recognition deficits observed in patients and mouse models (both schizophrenia-related and -unrelated) are discussed here in terms of the dual-process theory of recognition, which postulates that there are two recognition mechanisms-recollection versus familiarity-that can be selectively impaired by brain lesions, neuropsychiatric conditions, and putatively, sleep and circadian rhythm disruption. However, based on this view, the findings from patient studies and studies using genetic mouse models (NRG1 deficiency) seem to be inconsistent with each other. schizophrenia patients are impaired at recollection (and to a lesser extent, familiarity judgments), but NRG1-deficient mice are impaired at familiarity-based object recognition, raising concerns regarding the validity of using these genetically modified mice to model recognition phenotypes observed in patients. This issue can be resolved in future animal studies by examining performance in different variants of the spontaneous recognition task-the standard, perirhinal cortex-dependent, object recognition task versus the hippocampus-dependent object-place recognition task-in order to see which of the two recognition mechanisms is more disrupted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 408 | J. Mol. Neurosci. 2015 May 56: 205-11 |
| PMID | 25529856 |
| Title | Genetic variability testing of neurodevelopmental genes in schizophrenic patients. |
| Abstract | This study investigated the associations between single nucleotide polymorphisms in the neurodevelopmental Disrupted In schizophrenia 1 (DISC1 ), neuregulin 1 (NRG1), brain-derived neurotrophic factor (BDNF) and NOTCH4 genes and the clinical symptoms and the occurrence of treatment-resistant schizophrenia in the Slovenian population. We included 138 schizophrenia patients, divided into treatment-responsive and treatment-resistant group and 94 healthy blood donors. All subjects were genotyped for eight polymorphisms (DISC1 rs6675281, DISC1 rs821616, NRG1 rs3735781, NRG1 rs3735782, NRG1 rs10503929, NRG1 rs3924999, BDNF rs6265, NOTCH rs367398) and investigated for associations with clinical variables. NOTCH4 rs367398 AA/AG was significantly associated with worse Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) score. NOTCH4 rs367398 was not statistically significantly associated with the occurrence of treatment-resistant schizophrenia after the correction for multiple testing. Our data indicate that NOTCH4 polymorphism can influence clinical symptoms in Slovenian patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 409 | Front Cell Neurosci 2015 -1 9: 472 |
| PMID | 26733804 |
| Title | ErbB4 in Laminated Brain Structures: A Neurodevelopmental Approach to Schizophrenia. |
| Abstract | The susceptibility genes for schizophrenia Neuregulin-1 (NRG1) and ErbB4 have critical functions during brain development and in the adult. Alterations in the ErbB4 signaling pathway cause a variety of neurodevelopmental defects including deficiencies in neuronal migration, synaptic plasticity, and myelination. I have used the ErbB4(-/-) HER4(heart) KO mice to study the neurodevelopmental insults associated to deficiencies in the NRG1-ErbB4 signaling pathway and their potential implication with brain disorders such as schizophrenia, a chronic psychiatric disease affecting 1% of the population worldwide. ErbB4 deletion results in an array of neurodevelopmental deficits that are consistent with a schizophrenic model. First, similar defects appear in multiple brain structures, from the cortex to the cerebellum. Second, these defects affect multiple aspects of brain development, from deficits in neuronal migration to impairments in excitatory/inhibitory systems, including reductions in brain volume, cortical and cerebellar heterotopias, alterations in number and distribution of specific subpopulations of interneurons, deficiencies in the astrocytic and oligodendrocytic lineages, and additional insults in major brain structures. This suggests that alterations in specific neurodevelopmental genes that play similar functions in multiple neuroanatomical structures might account for some of the symptomatology observed in schizophrenic patients, such as defects in cognition. ErbB4 mutation uncovers flaws in brain development that are compatible with a neurodevelopmental model of schizophrenia, and it establishes a comprehensive model to study the basis of the disorder before symptoms are detected in the adult. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 410 | Pharmacogenet. Genomics 2015 Apr 25: 173-85 |
| PMID | 25714000 |
| Title | Large-scale candidate gene study to identify genetic risk factors predictive of paliperidone treatment response in patients with schizophrenia. |
| Abstract | Clinical response to antipsychotic medications can vary markedly in patients with schizophrenia. Identifying genetic variants associated with treatment response could help optimize patient care and outcome. To this end, we carried out a large-scale candidate gene study to identify genetic risk factors predictive of paliperidone efficacy. A central nervous system custom chip containing single nucleotide polymorphisms from 1204 candidate genes was utilized to genotype a discovery cohort of 684 schizophrenia patients from four clinical studies of paliperidone extended-release and paliperidone palmitate. Variants predictive of paliperidone efficacy were identified and further tested in four independent replication cohorts of schizophrenic patients (N=2856). We identified an SNP in ERBB4 that may contribute toward differential treatment response to paliperidone. The association trended in the same direction as the discovery cohort in two of the four replication cohorts, but ultimately did not survive multiple testing corrections. The association was not replicated in the other two independent cohorts. We also report several SNPs in well-known schizophrenia candidate genes that show suggestive associations with paliperidone efficacy. These preliminary findings suggest that genetic variation in the ERBB4 gene may differentially affect treatment response to paliperidone in individuals with schizophrenia. They implicate the neuregulin 1 (NRG1)-ErbB4 pathway for modulating antipsychotic response. However, these findings were not robustly reproduced in replication cohorts. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 411 | Mol. Psychiatry 2015 Oct 20: 1251-60 |
| PMID | 25349163 |
| Title | Calcyon stimulates neuregulin 1 maturation and signaling. |
| Abstract | Neuregulin1 (NRG1) is a single transmembrane protein that plays a critical role in neural development and synaptic plasticity. Both NRG1 and its receptor, ErbB4, are well-established risk genes of schizophrenia. The NRG1 ecto-domain (ED) binds and activates ErbB4 following proteolytic cleavage of pro-NRG1 precursor protein. Although several studies have addressed the function of NRG1 in brain, very little is known about the cleavage and shedding mechanism. Here we show that the neuronal vesicular protein calcyon is a potent activator and key determinant of NRG1 ED cleavage and shedding. Calcyon stimulates clathrin-mediated endocytosis and endosomal targeting; and its levels are elevated in postmortem brains of schizophrenics. Overexpression of calcyon stimulates NRG1 cleavage and signaling in vivo, and as a result, GABA transmission is enhanced in calcyon overexpressing mice. Conversely, NRG1 cleavage, ErbB4 activity and GABA transmission are decreased in calcyon null mice. Moreover, stimulation of NRG1 cleavage by calcyon was recapitulated in HEK 293 cells suggesting the mechanism involved is cell-autonomous. Finally, studies with site-specific mutants in calcyon and inhibitors for the major sheddases indicate that the stimulatory effects of calcyon on NRG1 cleavage and shedding depend on clathrin-mediated endocytosis, ?-secretase 1, and interaction with clathrin adaptor proteins. Together these results identify a novel mechanism for NRG1 cleavage and shedding. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 412 | Psychiatr. Genet. 2015 Aug 25: 147-54 |
| PMID | 25967537 |
| Title | Effects of genetic variations in NRG1 on cognitive domains in patients with schizophrenia and healthy individuals. |
| Abstract | The neuregulin 1 (NRG1) gene has been investigated as a candidate susceptibility gene for schizophrenia. A number of studies have also explored the genetic effect of NRG1 on cognitive deficits related to schizophrenia, and thus far generated inconsistent results. The current study aimed to determine whether genetic variations in NRG1 are associated with cognitive domains in schizophrenic patients and healthy individuals. Comprehensive neuropsychological tests composed of six cognitive domains were administered to 135 clinically stable patients with schizophrenia and 119 healthy individuals. On the basis of previous reports of positive association, a total of four single nucleotide polymorphisms were analyzed. In testing the genotype effect on cognitive domains, we used repeated-measure analysis for six cognitive domain scores of each individual as repeated measurements. An association of P-value less than 0.05 with at least one cognitive domain in patients and/or healthy individuals was observed for all of the single nucleotide polymorphisms. After applying the correction for multiple testing, the association remained statistically significant between rs6994992 and general cognitive ability (g) in the patient group and between rs2439272 and the 'working memory' domain in the group of healthy participants. This study suggests the involvement of NRG1 in the susceptibility for developing cognitive deficits in schizophrenic patients. For some cognitive domains, its genetic effect was also significant in generating interindividual variability within the normal functional range. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 413 | Mol Genet Genomic Med 2016 Jan 4: 18-27 |
| PMID | 26788534 |
| Title | Evaluation of genetic association of neurodevelopment and neuroimmunological genes with antipsychotic treatment response in schizophrenia in Indian populations. |
| Abstract | Neurodevelopmental and neuroimmunological genes critically regulate antipsychotic treatment outcome. We report genetic associations of antipsychotic response in 742 schizophrenia patients from Indian populations of Indo-European and Dravidian ancestry, segregated by disease severity. Meta-analysis comparing the two populations identified CCL2 [rs4795893: OR (95% CI) = 1.79 (1.27-2.52), P = 7.62 × 10(-4); rs4586: OR (95% CI) = 1.74 (1.24-2.43), P = 1.13 × 10(-3)] and GRIA4 [rs2513265: OR (95% CI) = 0.53 (0.36-0.78), P = 1.44 × 10(-3)] in low severity group; and, ADCY2 [rs1544938: OR (95% CI) = 0.36 (0.19-0.65), P = 7.68 × 10(-4)] and NRG1 [rs13250975, OR (95% CI) = 0.42 (0.23-0.79), P = 6.81 × 10(-3); rs17716295, OR (95% CI) = 1.78 (1.15-2.75), P = 8.71 × 10(-3)] in high severity group, with incomplete response toward antipsychotics. To our knowledge, this is the first study to identify genetic polymorphisms associated with the efficacy of antipsychotic treatment of schizophrenia patients from two major India populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 414 | J Toxicol Sci 2016 -1 41: 303-9 |
| PMID | 26961615 |
| Title | Effects of prolonged antipsychotic administration on neuregulin-1/ErbB signaling in rat prefrontal cortex and myocardium: implications for the therapeutic action and cardiac adverse effect. |
| Abstract | Patients with schizophrenia (SCZ) are at higher risk for developing cardiovascular disease (CVD) and neuregulin-1 (NRG1)/ErbB signaling has been identified as a common susceptibility pathway for the comorbidity. Antipsychotic treatment can change NRG1/ErbB signaling in the brain, which has been implicated in their therapeutic actions, whereas the drug-induced alterations of NRG1/ErbB pathway in cardiovascular system might be associated with the prominent cardiac side-effects of antipsychotic medication. To test this hypothesis, we examined NRG1/ErbB system in rat prefrontal cortex (PFC) and myocardium following 4-week intraperitoneal administration of haloperidol, risperidone or clozapine. Generally, the antipsychotics significantly enhanced NRG1/ErbB signaling with increased expression of NRG1 and phosphorylation of ErbB4 and ErbB2 in the brain and myocardium, except that clozapine partly blocked the cardiac NRG1/ErbB2 activation, which could be associated with its more severe cardiac adverse actions. Combined, our data firstly showed evidence of the effect of antipsychotic exposure on myocardial NRG1/ErbB signaling, along with the activated NRG1/ErbB system in brain, providing a potential link between the therapeutic actions and cardiotoxicity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 415 | Acta Neuropsychiatr 2016 Feb 28: 1-10 |
| PMID | 25877668 |
| Title | Transcranial direct current stimulation and neuroplasticity genes: implications for psychiatric disorders. |
| Abstract | Transcranial direct current stimulation (tDCS) is a non-invasive and well-tolerated brain stimulation technique with promising efficacy as an add-on treatment for schizophrenia and for several other psychiatric disorders. tDCS modulates neuroplasticity; psychiatric disorders are established to be associated with neuroplasticity abnormalities. This review presents the summary of research on potential genetic basis of neuroplasticity-modulation mechanism underlying tDCS and its implications for treating various psychiatric disorders. A systematic review highlighting the genes involved in neuroplasticity and their role in psychiatric disorders was carried out. The focus was on the established genetic findings of tDCS response relationship with BDNF and COMT gene polymorphisms. Synthesis of these preliminary observations suggests the potential influence of neuroplastic genes on tDCS treatment response. These include several animal models, pharmacological studies, mentally ill and healthy human subject trials. Taking into account the rapidly unfolding understanding of tDCS and the role of synaptic plasticity disturbances in neuropsychiatric disorders, in-depth evaluation of the mechanism of action pertinent to neuroplasticity modulation with tDCS needs further systematic research. Genes such as NRG1, DISC1, as well as those linked with the glutamatergic receptor in the context of their direct role in the modulation of neuronal signalling related to neuroplasticity aberrations, are leading candidates for future research in this area. Such research studies might potentially unravel observations that might have potential translational implications in psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 416 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016 Mar 171: 181-202 |
| PMID | 26462458 |
| Title | Currently recognized genes for schizophrenia: High-resolution chromosome ideogram representation. |
| Abstract | A large body of genetic data from schizophrenia-related research has identified an assortment of genes and disturbed pathways supporting involvement of complex genetic components for schizophrenia spectrum and other psychotic disorders. Advances in genetic technology and expanding studies with searchable genomic databases have led to multiple published reports, allowing us to compile a master list of known, clinically relevant, or susceptibility genes contributing to schizophrenia. We searched key words related to schizophrenia and genetics from peer-reviewed medical literature sources, authoritative public access psychiatric websites and genomic databases dedicated to gene discovery and characterization of schizophrenia. Our list of 560 genes were arranged in alphabetical order in tabular form with gene symbols placed on high-resolution human chromosome ideograms. Genome wide pathway analysis using GeneAnalytics was carried out on the resulting list of genes to assess the underlying genetic architecture for schizophrenia. Recognized genes of clinical relevance, susceptibility or causation impact a broad range of biological pathways and mechanisms including ion channels (e.g., CACNA1B, CACNA1C, CACNA1H), metabolism (e.g., CYP1A2, CYP2C19, CYP2D6), multiple targets of neurotransmitter pathways impacting dopamine, GABA, glutamate, and serotonin function, brain development (e.g., NRG1, RELN), signaling peptides (e.g., PIK3CA, PIK4CA) and immune function (e.g., HLA-DRB1, HLA-DQA1) and interleukins (e.g., IL1A, IL10, IL6). This summary will enable clinical and laboratory geneticists, genetic counselors, and other clinicians to access convenient pictorial images of the distribution and location of contributing genes to inform diagnosis and gene-based treatment as well as provide risk estimates for genetic counseling of families with affected relatives. © 2015 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 417 | Psychiatry Clin. Neurosci. 2016 Jun 70: 227-44 |
| PMID | 26969211 |
| Title | Biological aspects and candidate biomarkers for psychotic bipolar disorder: A systematic review. |
| Abstract | We carried out a systematic review of the available literature about potential biomarkers of psychotic bipolar disorder (BD-P), a specific subset presenting worse outcome and greater risk of relapse than non-psychotic bipolar disorder (BD-NP). We searched the main psychiatric databases (PubMed, ISI Web of Knowledge, PsychInfo). Only original articles with the main topic of BD-P compared to schizophrenia/BD-NP/healthy controls (HC) written in English from 1994 to 2015 were included. BD-P patients presented higher kynurenic acid levels in the cerebrospinal fluid, elevated anti- S accharomyces cerevisiae antibodies levels, and lower serum levels of dehydroepiandrosterone sulfate and progesterone than BD-NP/HC. Event-related potentials abnormalities have been identified in BD-P with respect to BD-NP. BD-P patients also presented bigger ventricles but similar hippocampal volumes compared to BD-NP/HC. Although the results are contrasting, some cognitive deficits seemed to be related to the psychotic dimension of bipolar affective disorder, such as impairment in verbal/logical memory, working memory, verbal and semantic fluency and executive functioning. Finally, polymorphisms of genes, such as NRG1, 5HTTLPR (s), COMT, DAOA and some chromosome regions (16p12 and 13q), were positively associated with BD-P. Data about the identification of specific biomarkers for BD-P are promising, but most of them have not yet been replicated. They could lead the clinicians to an early diagnosis and proper treatment, thus ameliorating outcome of BD-P and reducing the biological changes associated with a long duration of illness. Further studies with bigger samples are needed to detect more specific biological markers of the psychotic dimension of bipolar affective disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 418 | Schizophr. Res. 2016 Jan 170: 30-40 |
| PMID | 26597662 |
| Title | Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study. |
| Abstract | The Consortium on the Genetics of schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 419 | Sci Rep 2016 -1 6: 22606 |
| PMID | 26935991 |
| Title | Perinatal Exposure to Neuregulin-1 Results in Disinhibition of Adult Midbrain Dopaminergic Neurons: Implication in Schizophrenia Modeling. |
| Abstract | Aberrant neuregulin-1 (NRG1) signals are suggested to associate with the neuropathophysiology of schizophrenia. Employing a mouse schizophrenia model established by neonatal neuregulin-1 challenge, we analysed postpubertal consequence of the NRG1 pretreatment for the electrophysiological property of nigral dopamine neurons. In vivo single unit recordings from anaesthetized NRG1-pretreated mice revealed increased spike bursting of nigral dopamine neurons. In slice preparations from NRG1-pretreated mice, spontaneous firing was elevated relative to controls. The relative increase in firing rates was abolished by a GABAA receptor antagonist. Whole-cell recording showed that perinatal NRG1 pretreatment diminished inhibitory miniature synaptic currents as well as GABAA receptor sensitivity. These results collectively suggest that perinatal exposure to neuregulin-1 results in the disinhibition of nigral dopamine neurons to influence their firing properties at the adult stage when the behavioral deficits are evident. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 420 | J. Neurochem. 2016 Jan 136: 234-49 |
| PMID | 26465092 |
| Title | Neurological dysfunctions associated with altered BACE1-dependent Neuregulin-1 signaling. |
| Abstract | Inhibition of BACE1 is being pursued as a therapeutic target to treat patients suffering from Alzheimer's disease because BACE1 is the sole ?-secretase that generates ?-amyloid peptide. Knowledge regarding other cellular functions of BACE1 is therefore critical for the safe use of BACE1 inhibitors in human patients. Neuregulin-1 (NRG1) is a BACE1 substrate and BACE1 cleavage of NRG1 is critical for signaling functions in myelination, remyelination, synaptic plasticity, normal psychiatric behaviors, and maintenance of muscle spindles. This review summarizes the most recent discoveries associated with BACE1-dependent NRG1 signaling in these areas. This body of knowledge will help to provide guidance for preventing unwanted NRG1-based side effects following BACE1 inhibition in humans. To initiate its signaling cascade, membrane anchored Neuregulin (Nrg), mainly type I and III ?1 NRG1 isoforms and Nrg3, requires ectodomain shedding. BACE1 is one of such indispensable sheddases to release the functional Nrg signaling fragment. The dependence of Nrg on the cleavage by BACE1 is best manifested by disrupting the critical role of Nrg in the control of axonal myelination, schizophrenic behaviors as well as the formation and maintenance of muscle spindles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 421 | J. Neurosci. 2016 Apr 36: 4859-75 |
| PMID | 27122041 |
| Title | Behavioral, Neurophysiological, and Synaptic Impairment in a Transgenic Neuregulin1 (NRG1-IV) Murine Schizophrenia Model. |
| Abstract | schizophrenia is a chronic, disabling neuropsychiatric disorder with complex genetic origins. The development of strategies for genome manipulation in rodents provides a platform for understanding the pathogenic role of genes and for testing novel therapeutic agents. Neuregulin 1 (NRG1), a critical developmental neurotrophin, is associated with schizophrenia. The NRG1 gene undergoes extensive alternative splicing and, to date, little is known about the neurobiology of a novel NRG1 isoform, NRG1-IV, which is increased in the brains of individuals with schizophrenia and associated with genetic risk variation. Here, we developed a transgenic mouse model (NRG1-IV/NSE-tTA) in which human NRG1-IV is selectively overexpressed in a neuronal specific manner. Using a combination of molecular, biochemical, electrophysiological, and behavioral analyses, we demonstrate that NRG1-IV/NSE-tTA mice exhibit abnormal behaviors relevant to schizophrenia, including impaired sensorimotor gating, discrimination memory, and social behaviors. These neurobehavioral phenotypes are accompanied by increases in cortical expression of the NRG1 receptor, ErbB4 and the downstream signaling target, PIK3-p110?, along with disrupted dendritic development, synaptic pathology, and altered prefrontal cortical excitatory-inhibitory balance. Pharmacological inhibition of p110? reversed sensorimotor gating and cognitive deficits. These data demonstrate a novel role for NRG1-IV in learning, memory, and neural circuit formation and a potential neurobiological mechanism for schizophrenia risk; show that deficits are pharmacologically reversible in adulthood; and further highlight p110? as a target for antipsychotic drug development. schizophrenia is a disabling psychiatric disorder with neurodevelopmental origins. Genes that increase risk for schizophrenia have been identified. Understanding how these genes affect brain development and function is necessary. This work is the first report of a newly generated humanized transgenic mouse model engineered to express human NRG1-IV, an isoform of the NRG1 (Neuregulin 1) gene that is increased in the brains of patients with schizophrenia in association with genetic risk. Using behavioral neuroscience, molecular biology, electrophysiology, and pharmacology, we identify a role for NRG1-IV in learning, memory, and cognition and determine that this relates to brain excitatory-inhibitory balance and changes in ErbB4/PI3K/AKT signaling. Moreover, the study further highlights the potential of targeting the PI3K pathway for the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 422 | Neurochem. Res. 2016 Apr -1: -1 |
| PMID | 27097547 |
| Title | Sub-chronic Antipsychotic Drug Administration Reverses the Expression of Neuregulin 1 and ErbB4 in a Cultured MK801-Induced Mouse Primary Hippocampal Neuron or a Neurodevelopmental Schizophrenia Model. |
| Abstract | It has been reported that specific environmental influences during the postpartum period might contribute to the development of schizophrenia (SZ). Administration of MK801 during early development led to persistent brain pathology. Glutamate decarboxylase 1 (GAD67) and parvalbumin (PV), and neuregulin 1 (NRG1)/ErbB4 signaling were closely associated with SZ pathology. We postulated therefore that NMDA receptor antagonists exposure during the postpartum period may be associated with expression dysregulation of some of the SZ candidate proteins. To test this, we used mouse primary hippocampal neurons and neonatal male mice treated with the NMDA receptor antagonist, MK801 at postnatal day 4 (P4) or P7, followed by the treatments of antipsychotic drugs (i.e., olanzapine, risperidone, and haloperidol). The expressions of GAD67, PV, NRG1, and ErbB4 in in vitro and in vivo SZ models were detected with Western blot analysis and immunohistochemistry, respectively. Behavioral tests (locomotion activity, social interaction, novel object recognition and prepulse inhibition) were measured. We found MK801 decreased the expression of GAD67, PV, NRG1 and ErbB4, and induced obvious behavioral alterations, while antipsychotics reversed these alterations. These results suggest that exposure to the NMDA receptor antagonist in early development may lead to long-lasting influence on the expression of specific proteins, such as GAD67, PV, NRG1, and ErbB4. Moreover, our results suggest that rescue of the activation of the NRG1/ErbB4 signaling pathway may be one of the mechanisms by which antipsychotic drugs have an antipsychotic effect. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 423 | Gene 2016 May -1: -1 |
| PMID | 27236031 |
| Title | Association of the DISC1 and NRG1 Genetic Polymorphisms with Schizophrenia in a Chinese Population. |
| Abstract | Polymorphisms in Disrupted-in-schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) might be associated with schizophrenia; however, the conclusions of relevant studies were inconsistent across different ethnic populations. This population-based case-control study was carried out to determine whether polymorphisms in these two genes could be associated with schizophrenia in the Chinese population. A case-control study of 248 schizophrenia patients and 236 controls was performed with the Sequenom MassARRAY platform. The results revealed that the DISC1 rs821616 heterozygous (AT vs. AA: adjusted OR, 1.98, 95%CI: 1.30-3.02) and co-dominant (AT/TT vs. AA: adjusted OR =1.94; 95%CI: 1.29-2.92) patterns were associated with increased risk for developing schizophrenia in all participants and subgroups (stratified by sex and age at onset), respectively. Moreover, in the male subgroup, the DISC1 rs821597 genotype GA or GA/AA exhibited increased risk of schizophrenia. For NRG1 polymorphisms, in the early onset subgroup (?25years), the rs3924999 G/G genotype was susceptible to schizophrenia. The interaction of DISC1 rs821616 T allele with the NRG1 rs3924999 A allele or that of DISC1 rs821597 A allele with NRG1 rs3924999 A allele had synergic effects on the development of schizophrenia. This study concluded that carriers of the DISC1 rs821616 T allele have increased risk for developing schizophrenia, and that the DISC1 rs821597 A allele was susceptible to schizophrenia for the male, and that there are marked interactions between the DISC1 rs821616 T and/or rs821597 A alleles and the NRG1 rs3924999 A allele for the development of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 424 | Psychiatry Clin. Neurosci. 2016 Feb -1: -1 |
| PMID | 26909665 |
| Title | Effects of NRG1 genotypes on orbitofrontal sulcogyral patterns in Japanese patients diagnosed with schizophrenia. |
| Abstract | Numerous reports have described differences in the distribution of orbitofrontal cortex (OFC) sulcogyral patterns between patients with schizophrenia (SZ patients) and healthy controls (HCs). Alterations in OFC morphology are also observed in those at high risk for developing SZ and in first-episode SZ, suggesting that genetic associations may be extant in determining OFC sulcogyral patterns. We investigated the association between single nucleotide polymorphisms (SNPs) in NRG1 and OFC sulcogyral patterns. A total of 59 Japanese patients diagnosed with SZ and 60 HCs were scanned on a 1.5T magnet. Patients were also assessed clinically. OFC sulcogyral patterns were evaluated for each participant, and genotyping was performed for four SNPs in NRG1 (SNP8NRG243177, SNP8NRG221533, SNP8NRG241930, and rs1081062). There were significant differences in the distribution of OFC sulcogyral patterns between SZ patients and HCs (?(2) ?=?6.52, p?=?0.038). SZ patients showed an increase in the frequency of Type III expression, which was associated with an earlier age of disease onset (??=?-0.302, F?=?4.948, p?=?0.030). Although no difference was found in genotype frequencies between SZ patients and HCs, an NRG1 SNP, SNP8NRG243177, was associated with Type II expression in SZ patients (??=?0.237, F?=?4.120, p?=?0.047). Our results suggest that OFC sulcogyral pattern formation in schizophrenia may be associated with NRG1 allele frequency, which is closely related to neurodevelopment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 425 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016 Apr 171: 468-78 |
| PMID | 26888291 |
| Title | Genetic association between NRG1 and schizophrenia, major depressive disorder, bipolar disorder in Han Chinese population. |
| Abstract | schizophrenia, major depressive disorder, and bipolar disorder are three major psychiatric disorders affecting around 0.66%, 3.3%, and 1.5% of the Han Chinese population respectively. Several genetic linkage analyses and genome wide association studies identified NRG1 as a susceptibility gene of schizophrenia, which was validated by its role in neurodevelopment, glutamate, and other neurotransmitter receptor expression regulation. To further investigate whether NRG1 is a shared risk gene for major depressive disorder, bipolar disorder as well as schizophrenia, we performed an association study among 1,248 schizophrenia cases, 1,056 major depression cases, 1,344 bipolar disorder cases, and 1,248 controls. Totally 15 tag SNPs were genotyped and analyzed, and no population stratification was found in our sample set. Among the sites, rs4236710 (corrected Pgenotye? =?0.015) and rs4512342 (Pallele? =?0.03, Pgenotye? =?0.045 after correction) were associated with schizophrenia, and rs2919375 (corrected Pgenotye? =?0.004) was associated with major depressive disorder. The haplotype rs4512342-rs6982890 showed association with schizophrenia (P?=?0.03 for haplotype "TC" after correction), and haplotype rs4531002-rs11989919 proved to be a shared risk factor for both major depressive disorder ("CC": corrected P?=?0.009) and bipolar disorder ("CT": corrected P?=?0.003). Our results confirmed that NRG1 was a shared common susceptibility gene for major mental disorders in Han Chinese population. © 2016 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 426 | Psychopharmacology (Berl.) 2016 Apr 233: 1349-59 |
| PMID | 26861891 |
| Title | mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia. |
| Abstract | An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored. We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-D-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia. Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions. In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine. We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 427 | Sci Rep 2016 -1 6: 19581 |
| PMID | 26781398 |
| Title | Olanzapine Prevents the PCP-induced Reduction in the Neurite Outgrowth of Prefrontal Cortical Neurons via NRG1. |
| Abstract | Accumulating evidence suggests that reducing neurite outgrowth and synaptic plasticity plays a critical role in the pathology of cognitive deficits in schizophrenia. The N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) can induce symptoms of schizophrenia as well as reduce dendritic spine density and neurite growth. The antipsychotic drug olanzapine may improve these deficits. This study aimed to investigate: (1) if olanzapine prevents PCP-induced suppression of neurite outgrowth and synaptic protein expression; (2) if olanzapine affects the Akt-GSK3 signaling pathway; and (3) the role of neuregulin 1 (NRG1) in this process. Immunofluorescence revealed that PCP treatment for 24?hours reduces both neurite length (28.5%) and the number of neurite branches (35.6%) in primary prefrontal cortical neuron cultures. PCP reduced protein and mRNA expressions of synaptophysin (24.9% and 23.2%, respectively) and PSD95 (31.5% and 21.4%, respectively), and the protein expression of p-Akt (26.7%) and p-GSK3? (35.2%). Olanzapine co-treatment prevented these PCP-induced effects in normal neurons but not in neurons from NRG1-knockout mice. These results indicate that NRG1 mediates the preventive effects of olanzapine on the PCP-induced impairment of neurite outgrowth and synaptic protein expression. This study provides potential targets for interventions on improving the efficacy of olanzapine on preventing cognitive deficits in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 428 | Genes Brain Behav. 2016 Mar 15: 295-304 |
| PMID | 26707035 |
| Title | Behavioural effects of high fat diet in a mutant mouse model for the schizophrenia risk gene neuregulin 1. |
| Abstract | schizophrenia patients are often obese or overweight and poor dietary choices appear to be a factor in this phenomenon. Poor diet has been found to have complex consequences for the mental state of patients. Thus, this study investigated whether an unhealthy diet [i.e. high fat diet (HFD)] impacts on the behaviour of a genetic mouse model for the schizophrenia risk gene neuregulin 1 (i.e. transmembrane domain NRG1 mutant mice: NRG1 HET). Female NRG1 HET and wild-type-like littermates (WT) were fed with either HFD or a control chow diet. The mice were tested for baseline (e.g. anxiety) and schizophrenia-relevant behaviours after 7 weeks of diet exposure. HFD increased body weight and impaired glucose tolerance in all mice. Only NRG1 females on HFD displayed a hyper-locomotive phenotype as locomotion-suppressive effects of HFD were only evident in WT mice. HFD also induced an anxiety-like response and increased freezing in the context and the cued version of the fear conditioning task. Importantly, CHOW-fed NRG1 females displayed impaired social recognition memory, which was absent in HFD-fed mutants. Sensorimotor gating deficits of NRG1 females were not affected by diet. In summary, HFD had complex effects on the behavioural phenotype of test mice and attenuated particular cognitive deficits of NRG1 mutant females. This topic requires further investigations thereby also considering other dietary factors of relevance for schizophrenia as well as interactive effects of diet with medication and sex. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 429 | Neuroscience 2016 Feb 314: 1-11 |
| PMID | 26628400 |
| Title | OSO paradigm--A rapid behavioral screening method for acute psychosocial stress reactivity in mice. |
| Abstract | Chronic psychosocial stress is an important environmental risk factor for the development of psychiatric diseases. However, studying the impact of chronic psychosocial stress in mice is time consuming and thus not optimally suited to 'screen' increasing numbers of genetically manipulated mouse models for psychiatric endophenotypes. Moreover, many studies focus on restraint stress, a strong physical stressor with limited relevance for psychiatric disorders. Here, we describe a simple and a rapid method based on the resident-intruder paradigm to examine acute effects of mild psychosocial stress in mice. The OSO paradigm (open field--social defeat--open field) compares behavioral consequences on locomotor activity, anxiety and curiosity before and after exposure to acute social defeat stress. We first evaluated OSO in male C57Bl/6 wildtype mice where a single episode of social defeat reduced locomotor activity, increased anxiety and diminished exploratory behavior. Subsequently, we applied the OSO paradigm to mouse models of two schizophrenia (SZ) risk genes. Transgenic mice with neuronal overexpression of Neuregulin-1 (NRG1) type III showed increased risk-taking behavior after acute stress exposure suggesting that NRG1 dysfunction is associated with altered affective behavior. In contrast, Tcf4 transgenic mice displayed a normal stress response which is in line with the postulated predominant contribution of TCF4 to cognitive deficits of SZ. In conclusion, the OSO paradigm allows for rapid screening of selected psychosocial stress-induced behavioral endophenotypes in mouse models of psychiatric diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 430 | J. Biol. Chem. 2016 Jan 291: 318-33 |
| PMID | 26574544 |
| Title | Proteolytic Processing of Neuregulin 1 Type III by Three Intramembrane-cleaving Proteases. |
| Abstract | Numerous membrane-bound proteins undergo regulated intramembrane proteolysis. Regulated intramembrane proteolysis is initiated by shedding, and the remaining stubs are further processed by intramembrane-cleaving proteases (I-CLiPs). Neuregulin 1 type III (NRG1 type III) is a major physiological substrate of ?-secretase (?-site amyloid precursor protein-cleaving enzyme 1 (BACE1)). BACE1-mediated cleavage is required to allow signaling of NRG1 type III. Because of the hairpin nature of NRG1 type III, two membrane-bound stubs with a type 1 and a type 2 orientation are generated by proteolytic processing. We demonstrate that these stubs are substrates for three I-CLiPs. The type 1-oriented stub is further cleaved by ?-secretase at an ?-like site five amino acids N-terminal to the C-terminal membrane anchor and at a ?-like site in the middle of the transmembrane domain. The ?-cleavage site is only one amino acid N-terminal to a Val/Leu substitution associated with schizophrenia. The mutation reduces generation of the NRG1 type III ?-peptide as well as reverses signaling. Moreover, it affects the cleavage precision of ?-secretase at the ?-site similar to certain Alzheimer disease-associated mutations within the amyloid precursor protein. The type 2-oriented membrane-retained stub of NRG1 type III is further processed by signal peptide peptidase-like proteases SPPL2a and SPPL2b. Expression of catalytically inactive aspartate mutations as well as treatment with 2,2'-(2-oxo-1,3-propanediyl)bis[(phenylmethoxy)carbonyl]-l-leucyl-l-leucinamide ketone inhibits formation of N-terminal intracellular domains and the corresponding secreted C-peptide. Thus, NRG1 type III is the first protein substrate that is not only cleaved by multiple sheddases but is also processed by three different I-CLiPs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 431 | Schizophr Bull 2016 Mar 42: 279-87 |
| PMID | 26316594 |
| Title | Meta-analysis of Positive and Negative Symptoms Reveals Schizophrenia Modifier Genes. |
| Abstract | Evidence suggests that genetic factors may influence both schizophrenia (Scz) and its clinical presentation. In recent years, genome-wide association studies (GWAS) have demonstrated considerable success in identifying risk loci. Detection of "modifier loci" has the potential to further elucidate underlying disease processes. We performed GWAS of empirically derived positive and negative symptom scales in Irish cases from multiply affected pedigrees and a larger, independent case-control sample, subsequently combining these into a large Irish meta-analysis. In addition to single-SNP associations, we considered gene-based and pathway analyses to better capture convergent genetic effects, and to facilitate biological interpretation of these findings. Replication and testing of aggregate genetic effects was conducted using an independent European-American sample. Though no single marker met the genome-wide significance threshold, genes and ontologies/pathways were significantly associated with negative and positive symptoms; notably, NKAIN2 and NRG1, respectively. We observed limited overlap in ontologies/pathways associated with different symptom profiles, with immune-related categories over-represented for negative symptoms, and addiction-related categories for positive symptoms. Replication analyses suggested that genes associated with clinical presentation are generalizable to non-Irish samples. These findings strongly support the hypothesis that modifier loci contribute to the etiology of distinct Scz symptom profiles. The finding that previously implicated "risk loci" actually influence particular symptom dimensions has the potential to better delineate the roles of these genes in Scz etiology. Furthermore, the over-representation of distinct gene ontologies/pathways across symptom profiles suggests that the clinical heterogeneity of Scz is due in part to complex and diverse genetic factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 432 | Eur. J. Hum. Genet. 2016 Mar 24: 381-6 |
| PMID | 26014434 |
| Title | Myelination-related genes are associated with decreased white matter integrity in schizophrenia. |
| Abstract | Disruptions in white matter (WM) tract structures have been implicated consistently in the pathophysiology of schizophrenia. Global WM integrity - as measured by fractional anisotropy (FA) - is highly heritable and may provide a good endophenotype for genetic studies of schizophrenia. WM abnormalities in schizophrenia are not localized to one specific brain region but instead reflect global low-level decreases in FA coupled with focal abnormalities. In this study, we sought to investigate whether functional gene sets associated with schizophrenia are also associated with WM integrity. We analyzed FA and genetic data from the Mind Research Network Clinical Imaging Consortium to study the effect of multiple oligodendrocyte gene sets on schizophrenia and WM integrity using a functional gene set analysis in 77 subjects with schizophrenia and 104 healthy controls. We found that a gene set involved in myelination was significantly associated with schizophrenia and FA. This gene set includes 17 genes that are expressed in oligodendrocytes and one neuronal gene (NRG1) that is known to regulate myelination. None of the genes within the gene set were associated with schizophrenia or FA individually, suggesting that no single gene was driving the association of the gene set. Our findings support the hypothesis that multiple genetic variants in myelination-related genes contribute to the observed correlation between schizophrenia and decreased WM integrity as measured by FA. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 433 | J. Neurochem. 2016 Jan 136: 234-49 |
| PMID | 26465092 |
| Title | Neurological dysfunctions associated with altered BACE1-dependent Neuregulin-1 signaling. |
| Abstract | Inhibition of BACE1 is being pursued as a therapeutic target to treat patients suffering from Alzheimer's disease because BACE1 is the sole ?-secretase that generates ?-amyloid peptide. Knowledge regarding other cellular functions of BACE1 is therefore critical for the safe use of BACE1 inhibitors in human patients. Neuregulin-1 (NRG1) is a BACE1 substrate and BACE1 cleavage of NRG1 is critical for signaling functions in myelination, remyelination, synaptic plasticity, normal psychiatric behaviors, and maintenance of muscle spindles. This review summarizes the most recent discoveries associated with BACE1-dependent NRG1 signaling in these areas. This body of knowledge will help to provide guidance for preventing unwanted NRG1-based side effects following BACE1 inhibition in humans. To initiate its signaling cascade, membrane anchored Neuregulin (Nrg), mainly type I and III ?1 NRG1 isoforms and Nrg3, requires ectodomain shedding. BACE1 is one of such indispensable sheddases to release the functional Nrg signaling fragment. The dependence of Nrg on the cleavage by BACE1 is best manifested by disrupting the critical role of Nrg in the control of axonal myelination, schizophrenic behaviors as well as the formation and maintenance of muscle spindles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |