| 1 | Schizophr. Res. 2004 May 68: 27-35 |
|---|---|
| PMID | 15037337 |
| Title | Facial recognition deficits and cognition in schizophrenia. |
| Abstract | Previous investigations have found impaired recognition of facial affect and cognition in schizophrenia. We compared patients with schizophrenia and healthy control volunteers on computerized tasks of emotion recognition, to determine whether emotion processing deficits were correlated with neurocognitive performance. A Computerized Neuropsychological Test Battery (CNP) was administered to 40 patients (25 male, 15 female, mean age+/-S.D. 30.4+/-8.1) with schizophrenia (DSM-IV, 15 first episode and 25 chronically ill patients) treated with atypical neuroleptics and 43 healthy volunteers. A German version of the PENN Facial Discrimination, Differentiation and Memory Test, including happy, sad and neutral faces was used. Additionally, all patients were tested with a standard neuropsychological battery and rated for positive and negative symptoms. Patients with schizophrenia performed worse than control subjects on all emotion recognition tasks (p<0.01). We found higher error rates for discrimination of emotion in happy (p<0.02) and happy female faces (p<0.01), for differentiation of sad versus happy faces (p<0.001) and for facial memory (p<0.04). Poorer performance in emotion discrimination and facial memory correlated with severity of negative symptoms, abstraction-flexibility (p<0.001), verbal memory (p<0.01) and language processing (p<0.001). The study did not reveal a specific deficit for emotion recognition in schizophrenia. These findings lend support to the notion that difficulties in emotion recognition are associated in schizophrenia with key cognitive deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Mol. Psychiatry 2005 Mar 10: 309-22 |
| PMID | 15303102 |
| Title | Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder. |
| Abstract | Major depressive disorder is one of the most common and devastating psychiatric disorders. To identify candidate mechanisms for major depressive disorder, we compared gene expression in the temporal cortex from 12 patients with major depressive disorder and 14 matched controls using Affymetrix HgU95A microarrays. Significant expression changes were revealed in families of genes involved in neurodevelopment, signal transduction and cell communication. Among these, the expression of 17 genes related to oligodendrocyte function was significantly (P < 0.05, fold change > 1.4) decreased in patients with major depressive disorder. Eight of these 17 genes encode structural components of myelin (CNP, MAG, MAL, MOG, MOBP, PMP22, PLLP, PLP1). Five other genes encode enzymes involved in the synthesis of myelin constituents (ASPA, UGT8), or are essential in regulation of myelin formation (ENPP2, EDG2, TF, KLK6). One gene, that is, SOX10, encodes a transcription factor regulating other myelination-related genes. OLIG2 is a transcription factor present exclusively in oligodendrocytes and oligodendrocyte precursors. Another gene, ERBB3, is involved in oligodendrocyte differentiation. In addition to myelination-related genes, there were significant changes in multiple genes involved in axonal growth/synaptic function. These findings suggest that major depressive disorder may be associated with changes in cell communication and signal transduction mechanisms that contribute to abnormalities in oligodendroglia and synaptic function. Taken together with other studies, these findings indicate that major depressive disorder may share common oligodendroglial abnormalities with schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Schizophr. Res. 2006 Dec 88: 245-50 |
| PMID | 17010574 |
| Title | The 2',3'-cyclic nucleotide 3'-phosphodiesterase and oligodendrocyte lineage transcription factor 2 genes do not appear to be associated with schizophrenia in the Japanese population. |
| Abstract | Several lines of evidence suggest that disturbance of myelin-related genes is associated with the etiology of schizophrenia. Recently, the 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) gene and the oligodendrocyte lineage transcription factor 2 (OLIG2) gene were reported to be related to the development of schizophrenia, based on the results of genetic association and microarray studies. In the present study, no significant association with schizophrenia was observed by single-marker or haplotype analysis for 6 tag SNPs of these genes (759 cases, 757 controls). These findings suggest that CNP and OLIG2 are unlikely to be related to the development of schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Neurobiol. Dis. 2006 Mar 21: 531-40 |
| PMID | 16213148 |
| Title | Myelin-associated mRNA and protein expression deficits in the anterior cingulate cortex and hippocampus in elderly schizophrenia patients. |
| Abstract | Microarray and other studies have reported oligodendrocyte and myelin-related (OMR) deficits in schizophrenia. Here, we employed a quantitative approach to determine the magnitude of OMR gene expression deficits and their brain-region specificity. In addition, we examined how expression levels among the studied OMR genes are interrelated. mRNA of MAG, CNP, SOX10, CLDN11, and PMP22, but not MBP and MOBP, was reduced in the hippocampus and anterior cingulate cortex but not in the putamen of patients with schizophrenia. Expression of the only protein examined (CNP) was decreased in the hippocampus but not in the putamen. Correlation and factor analyses revealed that mRNA levels for genes that did exhibit differential expression in schizophrenia (MAG, CNP, SOX10, CLDN11, and PMP2), as opposed to those that did not (MOBP and MBP), loaded on separate factors. Thus, OMR gene and protein expression deficits in schizophrenia are brain-region specific, and the affected components may share regulatory elements. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | 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 |
| 6 | Arch. Gen. Psychiatry 2006 Jan 63: 18-24 |
| PMID | 16389193 |
| Title | Convergent evidence for 2',3'-cyclic nucleotide 3'-phosphodiesterase as a possible susceptibility gene for schizophrenia. |
| Abstract | Convergent data make 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) a candidate gene for schizophrenia. Reduced expression has been reported in the schizophrenic brain. The CNP gene maps to a region to which we have reported linkage to schizophrenia. Mice in which the CNP gene has been knocked out display central nervous system pathological characteristics reminiscent of some features observed in schizophrenia. 2',3'-Cyclic nucleotide 3'-phosphodiesterase is used as a marker of myelin-forming cells and is detectable in cells of oligodendrocyte lineage throughout life. Because CNP is thought to be important for oligodendrocyte function, altered expression has been interpreted as supportive of the hypothesis that altered oligodendrocyte function may be an etiological factor in schizophrenia. However, it is unclear whether the observed changes in the schizophrenic brain are primary or secondary. To determine if CNP expression is influenced by DNA polymorphisms and to verify if these polymorphisms are associated with schizophrenia. Allele-specific messenger RNA expression assay and genetic association studies. Unrelated subjects were ascertained from secondary psychiatric inpatient and outpatient services. We used brain tissue from 60 anonymous individuals with no known psychiatric disorder; a case-control sample of 708 white individuals from the United Kingdom meeting DSM-IV criteria for schizophrenia matched for age, sex, and ethnicity to 711 blood donor controls; and a pedigree with DNA from 6 affected siblings and 1 parent, showing evidence for linkage to CNP. Association between allele and gene expression. Association between allele and schizophrenia. The exonic single nucleotide polymorphism rs2070106 was associated with CNP expression (P<.001). Compatible with underexpression of CNP messenger RNA in schizophrenia, the lower-expressing A allele was significantly associated with schizophrenia (P = .04) in the case-control sample. All affected individuals in the linked pedigree were homozygous for the lower-expression allele, providing independent support for the association (P = .03). Our data support the hypothesis that reduced CNP expression in the schizophrenic brain is relevant to disease etiology and therefore provide support for the general hypothesis that altered oligodendrocyte function is an etiological factor in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Arch. Gen. Psychiatry 2006 Jan 63: 18-24 |
| PMID | 16389193 |
| Title | Convergent evidence for 2',3'-cyclic nucleotide 3'-phosphodiesterase as a possible susceptibility gene for schizophrenia. |
| Abstract | Convergent data make 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) a candidate gene for schizophrenia. Reduced expression has been reported in the schizophrenic brain. The CNP gene maps to a region to which we have reported linkage to schizophrenia. Mice in which the CNP gene has been knocked out display central nervous system pathological characteristics reminiscent of some features observed in schizophrenia. 2',3'-Cyclic nucleotide 3'-phosphodiesterase is used as a marker of myelin-forming cells and is detectable in cells of oligodendrocyte lineage throughout life. Because CNP is thought to be important for oligodendrocyte function, altered expression has been interpreted as supportive of the hypothesis that altered oligodendrocyte function may be an etiological factor in schizophrenia. However, it is unclear whether the observed changes in the schizophrenic brain are primary or secondary. To determine if CNP expression is influenced by DNA polymorphisms and to verify if these polymorphisms are associated with schizophrenia. Allele-specific messenger RNA expression assay and genetic association studies. Unrelated subjects were ascertained from secondary psychiatric inpatient and outpatient services. We used brain tissue from 60 anonymous individuals with no known psychiatric disorder; a case-control sample of 708 white individuals from the United Kingdom meeting DSM-IV criteria for schizophrenia matched for age, sex, and ethnicity to 711 blood donor controls; and a pedigree with DNA from 6 affected siblings and 1 parent, showing evidence for linkage to CNP. Association between allele and gene expression. Association between allele and schizophrenia. The exonic single nucleotide polymorphism rs2070106 was associated with CNP expression (P<.001). Compatible with underexpression of CNP messenger RNA in schizophrenia, the lower-expressing A allele was significantly associated with schizophrenia (P = .04) in the case-control sample. All affected individuals in the linked pedigree were homozygous for the lower-expression allele, providing independent support for the association (P = .03). Our data support the hypothesis that reduced CNP expression in the schizophrenic brain is relevant to disease etiology and therefore provide support for the general hypothesis that altered oligodendrocyte function is an etiological factor in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Neurosci. Lett. 2007 Apr 416: 113-6 |
| PMID | 17306456 |
| Title | Case-control association study of the 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) gene and schizophrenia in the Han Chinese population. |
| Abstract | Converging evidence from imaging, microarray, genetic, and other studies suggests that abnormalities in myelin may play a role in schizophrenia. The expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), which is used as a myelin marker, has been reported to be reduced in the schizophrenic brain. A synonymous genetic variation in the CNP gene, rs2070106, has recently been shown to be associated with schizophrenia in Caucasians. The present study investigates whether this finding can be replicated in the Han Chinese population. We performed an association analysis of four ht-SNPs in the CNP gene in a Chinese sample consisting of 426 schizophrenic patients and 439 healthy controls. We did not find any significant differences in any genotypic, allelic or haplotypic distributions between patients and controls. Therefore, this study did not find an association between genetic variations in the CNP gene and schizophrenia in the Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Neurosci. Lett. 2007 Apr 416: 113-6 |
| PMID | 17306456 |
| Title | Case-control association study of the 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) gene and schizophrenia in the Han Chinese population. |
| Abstract | Converging evidence from imaging, microarray, genetic, and other studies suggests that abnormalities in myelin may play a role in schizophrenia. The expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), which is used as a myelin marker, has been reported to be reduced in the schizophrenic brain. A synonymous genetic variation in the CNP gene, rs2070106, has recently been shown to be associated with schizophrenia in Caucasians. The present study investigates whether this finding can be replicated in the Han Chinese population. We performed an association analysis of four ht-SNPs in the CNP gene in a Chinese sample consisting of 426 schizophrenic patients and 439 healthy controls. We did not find any significant differences in any genotypic, allelic or haplotypic distributions between patients and controls. Therefore, this study did not find an association between genetic variations in the CNP gene and schizophrenia in the Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Mar 144B: 129-58 |
| PMID | 17266109 |
| Title | Towards understanding the schizophrenia code: an expanded convergent functional genomics approach. |
| Abstract | Identifying genes for schizophrenia through classical genetic approaches has proven arduous. Here, we present a comprehensive convergent analysis that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a psychomimetic agent - phencyclidine (PCP), and an anti-psychotic - clozapine), with human genetic linkage data and human postmortem brain data, as a Bayesian strategy of cross validating findings. Topping the list of candidate genes, we have three genes involved in GABA neurotransmission (GABRA1, GABBR1, and GAD2), one gene involved in glutamate neurotransmission (GRIA2), one gene involved in neuropeptide signaling (TAC1), two genes involved in synaptic function (SYN2 and KCNJ4), six genes involved in myelin/glial function (CNP, MAL, MBP, PLP1, MOBP and GFAP), and one gene involved in lipid metabolism (LPL). These data suggest that schizophrenia is primarily a disorder of brain functional and structural connectivity, with GABA neurotransmission playing a prominent role. These findings may explain the EEG gamma band abnormalities detected in schizophrenia. The analysis also revealed other high probability candidates genes (neurotransmitter signaling, other structural proteins, ion channels, signal transduction, regulatory enzymes, neuronal migration/neurite outgrowth, clock genes, transcription factors, RNA regulatory genes), pathways and mechanisms of likely importance in pathophysiology. Some of the pathways identified suggest possible avenues for augmentation pharmacotherapy of schizophrenia with other existing agents, such as benzodiazepines, anticonvulsants and lipid modulating agents. Other pathways are new potential targets for drug development. Lastly, a comparison with our earlier work on bipolar disorder illuminates the significant molecular overlap between schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Schizophr. Res. 2007 Feb 90: 15-27 |
| PMID | 17223013 |
| Title | Expression of transcripts for myelination-related genes in the anterior cingulate cortex in schizophrenia. |
| Abstract | Several recent studies have found changes in the expression of genes functionally related to myelination and oligodendrocyte homeostasis in schizophrenia. These studies utilized microarrays and quantitative PCR (QPCR), methodologies which do not permit direct, unamplified examination of mRNA expression. In addition, these studies generally only examined transcript expression in homogenates of gray matter. In the present study, we examined the expression of myelination-related genes previously implicated in schizophrenia by microarray or QPCR. Using in situ hybridization, we measured transcript expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), myelin-associated glycoprotein (MAG), transferrin (TF), quaking (QKI), gelsolin, myelin oligodendrocyte glycoprotein, v-erb-b2 erythroblastic leukemia viral oncogene homolog 3, erbb2 interacting protein, motility-related protein-1, SRY-box containing gene 10, oligodendrocyte transcription factor 2, peripheral myelin protein 22, and claudin-11 in both gray and white matter of the anterior cingulate cortex (ACC) in subjects with schizophrenia (n=41) and a comparison group (n=34). We found decreased expression of MAG, QKI, TF, and CNP transcripts in white matter. We did not find any differences in expression of these transcripts between medicated (n=31) and unmedicated (n=10) schizophrenics, suggesting that these changes are not secondary to treatment with antipsychotics. Finally, we found significant positive correlations between QKI and MAG or CNP mRNA expression, suggesting that the transcription factor QKI regulates MAG and CNP expression. Our results support the hypothesis that myelination and oligodendrocyte function are impaired in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Schizophr. Res. 2007 Feb 90: 15-27 |
| PMID | 17223013 |
| Title | Expression of transcripts for myelination-related genes in the anterior cingulate cortex in schizophrenia. |
| Abstract | Several recent studies have found changes in the expression of genes functionally related to myelination and oligodendrocyte homeostasis in schizophrenia. These studies utilized microarrays and quantitative PCR (QPCR), methodologies which do not permit direct, unamplified examination of mRNA expression. In addition, these studies generally only examined transcript expression in homogenates of gray matter. In the present study, we examined the expression of myelination-related genes previously implicated in schizophrenia by microarray or QPCR. Using in situ hybridization, we measured transcript expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), myelin-associated glycoprotein (MAG), transferrin (TF), quaking (QKI), gelsolin, myelin oligodendrocyte glycoprotein, v-erb-b2 erythroblastic leukemia viral oncogene homolog 3, erbb2 interacting protein, motility-related protein-1, SRY-box containing gene 10, oligodendrocyte transcription factor 2, peripheral myelin protein 22, and claudin-11 in both gray and white matter of the anterior cingulate cortex (ACC) in subjects with schizophrenia (n=41) and a comparison group (n=34). We found decreased expression of MAG, QKI, TF, and CNP transcripts in white matter. We did not find any differences in expression of these transcripts between medicated (n=31) and unmedicated (n=10) schizophrenics, suggesting that these changes are not secondary to treatment with antipsychotics. Finally, we found significant positive correlations between QKI and MAG or CNP mRNA expression, suggesting that the transcription factor QKI regulates MAG and CNP expression. Our results support the hypothesis that myelination and oligodendrocyte function are impaired in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Psychiatr. Genet. 2008 Jun 18: 143-6 |
| PMID | 18496213 |
| Title | A family-based association study of the myelin-associated glycoprotein and 2',3'-cyclic nucleotide 3'-phosphodiesterase genes with schizophrenia. |
| Abstract | A recent surge of evidence implicating myelin abnormalities in the etiology of schizophrenia has been found. This study is a family-based genetic association analysis examining the myelin-associated glycoprotein (MAG) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) genes in schizophrenia. About 246 families of primarily European-Caucasian origin were genotyped for MAG rs2301600, rs720308, rs720309, rs756796, and CNP rs2070106 single nucleotide polymorphisms (SNPs). The FBAT program (v1.7.2) and Transmit were used to analyze individual SNPs and haplotypes, respectively. The CNP SNP (rs2070106) was potentially associated with schizophrenia (P=0.027). MAG variants were not associated with disease transmission based on single marker or haplotype analysis. A significant maternal parent-of-origin effect for the CNP risk allele for schizophrenia was found (P=0.003). No CNP-MAG gene-gene interaction conferred increased risk for schizophrenia. Our finding provides support for potential association of the CNP gene but not the MAG gene in schizophrenia in a Caucasian population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Psychiatry Clin. Neurosci. 2008 Feb 62: 103-8 |
| PMID | 18289148 |
| Title | Effect of a functional single nucleotide polymorphism in the 2',3'-cyclic nucleotide 3'-phosphodiesterase gene on the expression of oligodendrocyte-related genes in schizophrenia. |
| Abstract | Although the expression of oligodendrocyte-related genes in post-mortem brains of patients with schizophrenia is consistently reported to be downregulated, the cause of the change remains unclear. The A-allele of rs2070106 within the 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), an oligodendrocyte-related gene, was reported to show reduced expression compared with the G-allele, and proposed to be associated with schizophrenia. The effect of the rs2070106 genotype on the expression of CNP and other oligodendrocyte-related genes was examined using data previously obtained from DNA microarray studies of post-mortem brains. It was found that the effect of rs2070106 genotype on the CNP expression was transcript specific, and that the genotype was not associated with the expression of other oligodendrocyte-related genes. The rs207016 genotype is not likely to contribute to the reported coordinated down-regulation of oligodendrococyte-related genes in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Schizophr. Res. 2008 Jan 98: 118-28 |
| PMID | 18029146 |
| Title | Schizophrenia and sex associated differences in the expression of neuronal and oligodendrocyte-specific genes in individual thalamic nuclei. |
| Abstract | Considerable evidence based on the study of postmortem brain tissue suggests deficits in both neuronal and myelin systems in schizophrenia (SZ). To date, the majority of the biochemical and molecular biological studies have focused on the cerebral cortex. Most information traveling to or from the cortex is relayed or synaptically gated through the thalamus, and numerous studies suggest structural and functional abnormalities in interconnected regions of the thalamus and cortex in SZ. The present study extends our gene expression studies of neuronal and myelin systems to the thalamus. Quantitative PCR was employed to assess the expression of 10 genes in 5 divisions of the thalamus which were precisely harvested using Laser Capture Microdissection. The divisions studied were present on coronal sections at the level of the centromedian nucleus (CMN) taken from 14 schizophrenic and 16 normal control postmortem brains. The genes examined were specific for oligodendrocytes (MAG, CNP, MBP), neurons (ENO2), glutamatergic neurons (VGlut1, VGlut2, PV, CB) or GABAergic neurons (GAD65, GAD67). Expression levels for each of these markers were quantitated and compared between diagnoses, between sexes, and across nuclei. CB was much more highly expressed in the CMN in SZs compared to NCs. No other diagnosis related differences in gene expression were observed. The expression levels of CNP and MAG, but not MBP, were highly correlated with one another and both, but not MBP, were much more highly expressed in females than in males in all thalamic divisions examined. All markers were differentially expressed across nuclei. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Schizophr. Res. 2008 Jan 98: 118-28 |
| PMID | 18029146 |
| Title | Schizophrenia and sex associated differences in the expression of neuronal and oligodendrocyte-specific genes in individual thalamic nuclei. |
| Abstract | Considerable evidence based on the study of postmortem brain tissue suggests deficits in both neuronal and myelin systems in schizophrenia (SZ). To date, the majority of the biochemical and molecular biological studies have focused on the cerebral cortex. Most information traveling to or from the cortex is relayed or synaptically gated through the thalamus, and numerous studies suggest structural and functional abnormalities in interconnected regions of the thalamus and cortex in SZ. The present study extends our gene expression studies of neuronal and myelin systems to the thalamus. Quantitative PCR was employed to assess the expression of 10 genes in 5 divisions of the thalamus which were precisely harvested using Laser Capture Microdissection. The divisions studied were present on coronal sections at the level of the centromedian nucleus (CMN) taken from 14 schizophrenic and 16 normal control postmortem brains. The genes examined were specific for oligodendrocytes (MAG, CNP, MBP), neurons (ENO2), glutamatergic neurons (VGlut1, VGlut2, PV, CB) or GABAergic neurons (GAD65, GAD67). Expression levels for each of these markers were quantitated and compared between diagnoses, between sexes, and across nuclei. CB was much more highly expressed in the CMN in SZs compared to NCs. No other diagnosis related differences in gene expression were observed. The expression levels of CNP and MAG, but not MBP, were highly correlated with one another and both, but not MBP, were much more highly expressed in females than in males in all thalamic divisions examined. All markers were differentially expressed across nuclei. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Schizophr. Res. 2008 Jan 98: 129-38 |
| PMID | 17964117 |
| Title | Expression of oligodendrocyte-associated genes in dorsolateral prefrontal cortex of patients with schizophrenia. |
| Abstract | Prior studies have found decreased mRNA expression of oligodendrocyte-associated genes in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia. However, it is unclear which specific genes are affected and whether the changes occur in the cortical white or grey matter. We assessed the mRNA expression levels of four oligodendrocyte-related genes: myelin-associated basic protein (MOBP), myelin-associated glycoprotein (MAG), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and oligodendrocyte-lineage transcription factor 2 (OLIG2) in DLPFC white and grey matter using quantitative-PCR (approximately 70 controls and approximately 30 patients with schizophrenia). We also examined the effects of high-risk polymorphisms in CNP and OLIG2 on mRNA levels of these genes. We found that genetic polymorphisms in CNP (rs2070106) and OLIG2 (rs1059004 and rs9653711), previously associated with schizophrenia, predicted low expression of these genes. Expression of MAG, CNP and OLIG2 did not differ between patients with schizophrenia and controls in the grey or white matter but MOBP mRNA levels were increased in the DLPFC white matter in patients with a history of substance abuse. MOBP and CNP protein in the white matter was not altered. Although previously reported reductions in the expression of myelin-related genes in the DLPFC were not detected, we show that individuals carrying risk-associated alleles in oligodendrocyte-related genes had relatively lower transcript levels. These data illustrate the importance of genetic background in gene expression studies in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Neuroscience 2009 Nov 164: 88-107 |
| PMID | 19450667 |
| Title | Challenges in phenotype definition in the whole-genome era: multivariate models of memory and intelligence. |
| Abstract | Refining phenotypes for the study of neuropsychiatric disorders is of paramount importance in neuroscience. Poor phenotype definition provides the greatest obstacle for making progress in disorders like schizophrenia, bipolar disorder, Attention Deficit/Hyperactivity Disorder (ADHD), and autism. Using freely available informatics tools developed by the Consortium for Neuropsychiatric Phenomics (CNP), we provide a framework for defining and refining latent constructs used in neuroscience research and then apply this strategy to review known genetic contributions to memory and intelligence in healthy individuals. This approach can help us begin to build multi-level phenotype models that express the interactions between constructs necessary to understand complex neuropsychiatric diseases. These results are available online through the http://www.phenowiki.org database. Further work needs to be done in order to provide consensus-building applications for the broadly defined constructs used in neuroscience research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | BMC Med. Genet. 2009 -1 10: 31 |
| PMID | 19348671 |
| Title | No relationship between 2',3'-cyclic nucleotide 3'-phosphodiesterase and schizophrenia in the Chinese Han population: an expression study and meta-analysis. |
| Abstract | 2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP), one of the promising candidate genes for schizophrenia, plays a key part in the oligodendrocyte function and in myelination. The present study aims to investigate the relationship between CNP and schizophrenia in the Chinese population and the effect of different factors on the expression level of CNP in schizophrenia. Five CNP single nucleotide polymorphisms (SNPs) were investigated in a Chinese Han schizophrenia case-control sample set (n = 180) using direct sequencing. The results were included in the following meta-analysis. Quantitative real-time polymerase chain reaction (PCR) was conducted to examine CNP expression levels in peripheral blood lymphocytes. Factors including gender, genotype, sub-diagnosis and antipsychotics-treatment were found not to contribute to the expression regulation of the CNP gene in schizophrenia. Our meta-analysis produced similar negative results. The results suggest that the CNP gene may not be involved in the etiology and pathology of schizophrenia in the Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Schizophr. Res. 2009 Jul 112: 54-64 |
| PMID | 19447584 |
| Title | Subcortical oligodendrocyte- and astrocyte-associated gene expression in subjects with schizophrenia, major depression and bipolar disorder. |
| Abstract | Deficits in the expression of oligodendrocyte and myelin genes have been described in numerous cortical regions in schizophrenia and affective disorders; however, relatively little attention has been paid to subcortical structures. Here we employed quantitative real time PCR to examine the mRNA expression of 17 genes that are expressed by oligodendrocyte precursors (OLPs) and their derivatives, including astrocytes. Four subcortical regions were examined (the anteroventral (AV) and mediodorsal thalamic nuclei (MDN), internal capsule (IC) and putamen (Put)) in postmortem material from subjects (age 25-68 at time of death) with no known psychiatric history (NCs) as well as in subjects with schizophrenia (SZ), major depressive disorder (MDD), and bipolar disorder (BPD). In all regions examined, genes expressed after the terminal differentiation of oligodendrocytes tended to have lower levels of mRNA expression in subjects with SZ compared to NCs. These differences were statistically significant across regions for four genes (CNP, GALC, MAG and MOG) and approached significance for TF. No genes were under expressed in MDD. Only TF was under expressed in BPD and only in the IC. In contrast, two astrocyte-associated genes (GFAP and ALDH1L1) had higher mean expression levels across regions in all psychiatric groups relative to NCs. These differences reached statistical significance for SZ and MDD relative to NCs. There were no age by diagnosis interactions. The majority of age regressions had negative slopes for the expression of oligodendrocyte-associated genes. GFAP but not ALDH1L1 expression was significantly and positively correlated with age in the MDN, AV and Put. Across subject groups the expression of both astrocyte genes was highly correlated with cumulative neuroleptic exposure in all regions except the Put. Significant positive correlations were also observed in some regions between cumulative neuroleptic exposure and the expression of genes associated with mature oligodendrocytes as well as with bipotential OLPs. Multiple negative correlations were observed between the mRNA expression of astrocyte genes and genes expressed by terminally differentiated oligodendrocytes. These data are discussed in the context of myelin turnover and potential effects of psychiatric illness as well as medications on the developmental fate of OLPs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | 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 |
| 22 | EMBO Mol Med 2012 Jun 4: 528-39 |
| PMID | 22473874 |
| Title | A myelin gene causative of a catatonia-depression syndrome upon aging. |
| Abstract | Severe mental illnesses have been linked to white matter abnormalities, documented by postmortem studies. However, cause and effect have remained difficult to distinguish. CNP (2',3'-cyclic nucleotide 3'-phosphodiesterase) is among the oligodendrocyte/myelin-associated genes most robustly reduced on mRNA and protein level in brains of schizophrenic, bipolar or major depressive patients. This suggests that CNP reduction might be critical for a more general disease process and not restricted to a single diagnostic category. We show here that reduced expression of CNP is the primary cause of a distinct behavioural phenotype, seen only upon aging as an additional 'pro-inflammatory hit'. This phenotype is strikingly similar in CNP heterozygous mice and patients with mental disease carrying the AA genotype at CNP SNP rs2070106. The characteristic features in both species with their partial CNP 'loss-of-function' genotype are best described as 'catatonia-depression' syndrome. As a consequence of perturbed CNP expression, mice show secondary low-grade inflammation/neurodegeneration. Analogously, in man, diffusion tensor imaging points to axonal loss in the frontal corpus callosum. To conclude, subtle white matter abnormalities inducing neurodegenerative changes can cause/amplify psychiatric diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Proteomics 2013 Dec 13: 3548-53 |
| PMID | 24167090 |
| Title | The human oligodendrocyte proteome. |
| Abstract | Myelination of the CNS is performed by oligodendrocytes (OLs), which have been implicated in brain disorders, such as multiple sclerosis and schizophrenia. We have used the human oligodendroglial cell line MO3.13 to establish an OL reference proteome database. Proteins were prefractionationated by SDS-PAGE and after in-gel digestion subjected to nanoflow LC-MS analysis. Approximately 11?600 unique peptides were identified and, after stringent filtering, resulted in 2290 proteins representing nine distinct biological processes and various molecular classes and functions. OL-specific proteins, such as myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), as well as other proteins involved in multiple sclerosis and schizophrenia were also identified and are discussed. Proteins of this dataset have also been classified according to their chromosomal origin for providing useful data to the Chromosome-centric Human Proteome Project (C-HPP). Given the importance of OLs in the etiology of demyelinating and oligodendrogial disorders, the MO3.13 proteome database is a valuable data resource. The MS proteomics data have been deposited to the ProteomeXchange with identifier PXD000263 (http://proteomecentral.proteomexchange.org/dataset/PXD000263). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Life Sci. 2013 Oct 93: 429-34 |
| PMID | 23973956 |
| Title | Antipsychotics promote the differentiation of oligodendrocyte progenitor cells by regulating oligodendrocyte lineage transcription factors 1 and 2. |
| Abstract | Oligodendrocyte/myelin abnormalities may be an important component of the pathogenesis found in schizophrenia. The aim of this current study was to examine the possible effects of the antipsychotic drugs (APDs) haloperidol (HAL), olanzapine (OLA), and quetiapine (QUE) on the development of oligodendroglial lineage cells. CG4 cells, an oligodendrocyte progenitor cell line, were treated with various concentrations of HAL, OLA, or QUE for specific periods. The proliferation and differentiation of the CG4 cells were measured. The regulation of CG4 cell differentiation by oligodendrocyte lineage transcription factors 1 and 2 (Olig1 and Olig2) was examined. The APDs used in this study had no effect on the proliferation of CG4 cells. The APDs elevated the expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), a specific marker of oligodendrocytes, and promoted the CG4 cells to differentiate into CNP positive oligodendrocytes. QUE and OLA increased the expression of both Olig1 and Olig2 whereas HAL only increased the expression of Olig2. Our findings suggest that oligodendrocyte development is a target of HAL, OLA, and QUE and provide further evidence of the important role of oligodendrocytes in the pathophysiology and treatment of schizophrenia. They also indicate that the expression level of oligodendrocyte/myelin-related genes could be profoundly affected by APDs, which should be considered in future studies aiming to measure the oligodendrocyte/myelin-related gene expressions in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | BioData Min 2014 -1 7: 11 |
| PMID | 25097666 |
| Title | Hypothesis exploration with visualization of variance. |
| Abstract | The Consortium for Neuropsychiatric Phenomics (CNP) at UCLA was an investigation into the biological bases of traits such as memory and response inhibition phenotypes-to explore whether they are linked to syndromes including ADHD, Bipolar disorder, and schizophrenia. An aim of the consortium was in moving from traditional categorical approaches for psychiatric syndromes towards more quantitative approaches based on large-scale analysis of the space of human variation. It represented an application of phenomics-wide-scale, systematic study of phenotypes-to neuropsychiatry research. This paper reports on a system for exploration of hypotheses in data obtained from the LA2K, LA3C, and LA5C studies in CNP. ViVA is a system for exploratory data analysis using novel mathematical models and methods for visualization of variance. An example of these methods is called VISOVA, a combination of visualization and analysis of variance, with the flavor of exploration associated with ANOVA in biomedical hypothesis generation. It permits visual identification of phenotype profiles-patterns of values across phenotypes-that characterize groups. Visualization enables screening and refinement of hypotheses about variance structure of sets of phenotypes. The ViVA system was designed for exploration of neuropsychiatric hypotheses by interdisciplinary teams. Automated visualization in ViVA supports 'natural selection' on a pool of hypotheses, and permits deeper understanding of the statistical architecture of the data. Large-scale perspective of this kind could lead to better neuropsychiatric diagnostics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | Eur Arch Psychiatry Clin Neurosci 2014 Mar 264: 121-9 |
| PMID | 23728937 |
| Title | Differential effects of antipsychotics on the development of rat oligodendrocyte precursor cells exposed to cuprizone. |
| Abstract | Cuprizone (CPZ) is a copper-chelating agent and has been shown to induce white matter damage in mice and rats. The compromised white matter and oligodendrocytes (OLs) respond to some antipsychotics in vivo. However, little is known about the effects of antipsychotics on cultured OLs in the presence of CPZ. The aim of this study was to examine effects of some antipsychotics on developing OLs in the presence of CPZ. Oligodendrocyte progenitor cells (OPCs) were prepared from rat embryos; OLs at different developing stages were labeled with specific antibodies; levels of CNP and MBP proteins in mature OLs were assessed by Western-blot analysis; malondialdehyde (MDA) levels and activity of catalase were evaluated as well for an assessment of oxidative stress and antioxidative status. In immunofluorescent staining, CPZ was shown to inhibit the differentiation of cultured OPCs into O4-positive cells, reduce the maturation of O4-positive cells into CNP- and MBP-positive cells, and decrease levels of CNP and MBP in mature OLs. These inhibitory effects of CPZ were ameliorated by clozapine and quetiapine (QUE), but not by haloperidol and olanzapine. Further experiments were performed to explore the mechanism of the protective effects of QUE. QUE attenuated the decreases in CNP and MBP in CPZ-treated OLs, and blocked the CPZ-induced increase in MDA and decrease in catalase activity in cultured OLs. These results are relevant to the pathophysiology and treatment of schizophrenia considering the aberrant white matter development and evidence suggesting the derangement of the oxidant and antioxidant defense system in some of the patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |