| 1 | Neurosci. Lett. 2000 Dec 296: 168-70 |
|---|---|
| PMID | 11109007 |
| Title | Mutation analysis of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia. |
| Abstract | Dysfunction of N-methyl-D-aspartate (NMDA) type ionotropic glutamate receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of the antagonist phencyclidine (PCP) and observation that mice expressing low levels of the N-methyl-D-aspartate receptor NR1 subunit exhibit behavioral alterations that may be ameliorated by neuroleptic drugs. Based on the hypothesis that some schizophrenic patients have functionally deficient mutation(s) of the gene encoding N-methyl-D-aspartate receptor NR1 subunit (GRIN1), we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the GRIN1 gene. Four variants, IVS2-22T>C, IVS2-12G>A, IVS4-34C>T, and 1719G/A (Pro516Pro), were identified. No non-synonymous mutation was detected. No significant association was suggested by case-control comparisons. Results indicate that genomic variations of the GRIN1 gene are not likely to be involved substantially in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Neurosci. Lett. 2000 Dec 296: 168-70 |
| PMID | 11109007 |
| Title | Mutation analysis of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia. |
| Abstract | Dysfunction of N-methyl-D-aspartate (NMDA) type ionotropic glutamate receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of the antagonist phencyclidine (PCP) and observation that mice expressing low levels of the N-methyl-D-aspartate receptor NR1 subunit exhibit behavioral alterations that may be ameliorated by neuroleptic drugs. Based on the hypothesis that some schizophrenic patients have functionally deficient mutation(s) of the gene encoding N-methyl-D-aspartate receptor NR1 subunit (GRIN1), we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the GRIN1 gene. Four variants, IVS2-22T>C, IVS2-12G>A, IVS4-34C>T, and 1719G/A (Pro516Pro), were identified. No non-synonymous mutation was detected. No significant association was suggested by case-control comparisons. Results indicate that genomic variations of the GRIN1 gene are not likely to be involved substantially in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Psychiatr. Genet. 2002 Dec 12: 225-30 |
| PMID | 12454527 |
| Title | Systematic mutation analysis of the human glutamate receptor, ionotropic, N-methyl-D-aspartate 1 gene(GRIN1) in schizophrenic patients. |
| Abstract | schizophrenia is a severe, complex mental disorder with unknown etiology. Abnormal glutamate neurotransmission has been proposed as one of the hypotheses of the pathogenesis of schizophrenia. Mohn recently reported that transgenic mice with the reduced glutamate receptor, ionotropic, -methyl-D-aspartate 1 gene (GRIN1) (formerly referred to as NMDAR1) expression display schizophrenia-like behaviors, which can be ameliorated by antipsychotic drug treatment. Their report promoted us to examine whether mutations in the human GRIN1 gene may convey genetic susceptibility to schizophrenia. To test this possibility, we systematically screened mutations in the promoter region and in all the exons of the human GRIN1 gene in a cohort of Chinese schizophrenic patients from Taiwan. Using single-strand conformation polymorphism analysis and autosequencing, we identified two single nucleotide polymorphisms, designated g.-1140G>A and g.-855G>C, respectively, at the 5'-untranslated region of the human GRIN1 gene. Genetic association study, however, revealed no association of these two single nucleotide polymorphisms with schizophrenia in our patients. Besides, no other mutations of the human GRIN1 gene were detected in this study. Our data suggest that the human GRIN1 gene may not contribute substantially to the genetic etiology of schizophrenia in our population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Psychiatr. Genet. 2002 Dec 12: 225-30 |
| PMID | 12454527 |
| Title | Systematic mutation analysis of the human glutamate receptor, ionotropic, N-methyl-D-aspartate 1 gene(GRIN1) in schizophrenic patients. |
| Abstract | schizophrenia is a severe, complex mental disorder with unknown etiology. Abnormal glutamate neurotransmission has been proposed as one of the hypotheses of the pathogenesis of schizophrenia. Mohn recently reported that transgenic mice with the reduced glutamate receptor, ionotropic, -methyl-D-aspartate 1 gene (GRIN1) (formerly referred to as NMDAR1) expression display schizophrenia-like behaviors, which can be ameliorated by antipsychotic drug treatment. Their report promoted us to examine whether mutations in the human GRIN1 gene may convey genetic susceptibility to schizophrenia. To test this possibility, we systematically screened mutations in the promoter region and in all the exons of the human GRIN1 gene in a cohort of Chinese schizophrenic patients from Taiwan. Using single-strand conformation polymorphism analysis and autosequencing, we identified two single nucleotide polymorphisms, designated g.-1140G>A and g.-855G>C, respectively, at the 5'-untranslated region of the human GRIN1 gene. Genetic association study, however, revealed no association of these two single nucleotide polymorphisms with schizophrenia in our patients. Besides, no other mutations of the human GRIN1 gene were detected in this study. Our data suggest that the human GRIN1 gene may not contribute substantially to the genetic etiology of schizophrenia in our population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Schizophr. Res. 2002 Nov 58: 83-6 |
| PMID | 12363394 |
| Title | Polymorphism analysis of the upstream region of the human N-methyl-D-aspartate receptor subunit NR1 gene (GRIN1): implications for schizophrenia. |
| Abstract | Dysfunction of the gene for the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor (GRIN1) has been implicated in the pathogenesis of schizophrenia. In support of this hypothesis are behavioral abnormalities reminiscent of schizophrenia in mice with an attenuated expression of the NR1 subunit receptor and the reduced level of NR1 mRNA in postmortem brains of patients with schizophrenia. We screened single nucleotide polymorphisms (SNPs) in the upstream region between +51 and -941 from the translation initiation codon of GRIN1 and identified 17 SNPs, 10 of which were located within the region containing the Sp1 motif and the GSG motifs. As genotyping of 191-196 Japanese patients with schizophrenia and 202-216 controls revealed no significant association between schizophrenia and the SNPs in the upstream region of GRIN1, these SNPs apparently do not play a critical role in the pathogenesis of schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | J. Neurosci. 2002 Aug 22: 6713-23 |
| PMID | 12151550 |
| Title | Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity. |
| Abstract | NMDA receptor hypofunction has been implicated in the pathophysiology of schizophrenia, and pharmacological and genetic approaches have been used to model such dysfunction. We previously have described two mouse lines carrying point mutations in the NMDA receptor glycine binding site, GRIN1(D481N) and GRIN1(K483Q), which exhibit 5- and 86-fold reductions in receptor glycine affinity, respectively. GRIN1(D481N) animals exhibit a relatively mild phenotype compatible with a moderate reduction in NMDA receptor function, whereas GRIN1(K483Q) animals die shortly after birth. In this study we have characterized compound heterozygote GRIN1(D481N/K483Q) mice, which are viable and exhibited biphasic NMDA receptor glycine affinities compatible with the presence of each of the two mutated alleles. GRIN1(D481N/K483Q) mice exhibited a marked NMDA receptor hypofunction revealed by deficits in hippocampal long-term potentiation, which were rescued by the glycine site agonist d-serine, which also facilitated NMDA synaptic currents in mutant, but not in wild-type, mice. Analysis of striatal monoamine levels revealed an apparent dopaminergic and serotonergic hyperfunction. Behaviorally, GRIN1(D481N/K483Q) mice were insensitive to acute dizocilpine pretreatment and exhibited increased startle response but normal prepulse inhibition. Most strikingly, mutant mice exhibited a sustained, nonhabituating hyperactivity and increased stereotyped behavior that were resistant to suppression by antipsychotics and the benzodiazepine site agonist Zolpidem. They also displayed a disruption of nest building behavior and were unable to perform a cued learning paradigm in the Morris water maze. We speculate that the severity of NMDA receptor hypofunction in these mice may account for their profound behavioral phenotype and insensitivity to antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Neuropsychobiology 2003 -1 47: 178-81 |
| PMID | 12824739 |
| Title | Association analysis of the genetic variants of the N-methyl D-aspartate receptor subunit 2b (NR2b) and treatment-refractory schizophrenia in the Chinese. |
| Abstract | Several pieces of evidence showed that N-methyl D-aspartate (NMDA)-receptor-mediated decreases in function may be a causative factor for schizophrenia. The NMDA receptors are composed of a common glutamate receptor, an ionotropic NMDA 1 (GRIN1) subunit and one of four GRIN2 subunits (GRIN2A-GRIN2D), combined in an undetermined ratio to make up the receptor complex. In this study, we tested the hypothesis of whether the GRIN2B 366C/G and 2664C/T genetic polymorphisms are related to Chinese treatment-refractory schizophrenic patients. 193 treatment-refractory schizophrenic patients and 176 normal subjects were recruited for this study. The results demonstrated that the genotype distribution was similar between schizophrenic patients and control subjects in 366C/G (p = 0.88) and 2664C/T (p = 0.336), but we found a higher mean clozapine dosage in 2664C/C genotype patients. These results show that GRIN2B genetic variations were not a major risk factor for treatment-refractory schizophrenic patients, but may influence the effect of clozapine during treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Neuropsychobiology 2003 -1 47: 178-81 |
| PMID | 12824739 |
| Title | Association analysis of the genetic variants of the N-methyl D-aspartate receptor subunit 2b (NR2b) and treatment-refractory schizophrenia in the Chinese. |
| Abstract | Several pieces of evidence showed that N-methyl D-aspartate (NMDA)-receptor-mediated decreases in function may be a causative factor for schizophrenia. The NMDA receptors are composed of a common glutamate receptor, an ionotropic NMDA 1 (GRIN1) subunit and one of four GRIN2 subunits (GRIN2A-GRIN2D), combined in an undetermined ratio to make up the receptor complex. In this study, we tested the hypothesis of whether the GRIN2B 366C/G and 2664C/T genetic polymorphisms are related to Chinese treatment-refractory schizophrenic patients. 193 treatment-refractory schizophrenic patients and 176 normal subjects were recruited for this study. The results demonstrated that the genotype distribution was similar between schizophrenic patients and control subjects in 366C/G (p = 0.88) and 2664C/T (p = 0.336), but we found a higher mean clozapine dosage in 2664C/C genotype patients. These results show that GRIN2B genetic variations were not a major risk factor for treatment-refractory schizophrenic patients, but may influence the effect of clozapine during treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Biol. Psychiatry 2003 Apr 53: 617-9 |
| PMID | 12679240 |
| Title | Association between the G1001C polymorphism in the GRIN1 gene promoter region and schizophrenia. |
| Abstract | The GRIN1 gene plays a fundamental role in many brain functions, and its involvement in the pathogenesis of the schizophrenia has been widely investigated. Non-synonymous polymorphisms have not been identified in the coding regions. To investigate the potential role of GRIN1 in the susceptibility to schizophrenia, we analyzed the G1001C polymorphism located in the promoter region in a case-control association study. The G1001C polymorphism allele distribution was analyzed in a sample of 139 Italian schizophrenic patients and 145 healthy control subjects by a polymerase chain reaction amplification followed by digestion with a restriction endonuclease. We found that the C allele may alter a consensus sequence for the transcription factor NF-kappa B and that its frequency was higher in patients than in control subjects (p =.0085). The genotype distribution also was different, with p =.034 (if C allele dominant, p =.0137, odds ratio 2.037, 95% confidence interval 1.1502-3.6076). The association reported in this study suggests that the GRIN1 gene is a good candidate for the susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Biol. Psychiatry 2003 Apr 53: 617-9 |
| PMID | 12679240 |
| Title | Association between the G1001C polymorphism in the GRIN1 gene promoter region and schizophrenia. |
| Abstract | The GRIN1 gene plays a fundamental role in many brain functions, and its involvement in the pathogenesis of the schizophrenia has been widely investigated. Non-synonymous polymorphisms have not been identified in the coding regions. To investigate the potential role of GRIN1 in the susceptibility to schizophrenia, we analyzed the G1001C polymorphism located in the promoter region in a case-control association study. The G1001C polymorphism allele distribution was analyzed in a sample of 139 Italian schizophrenic patients and 145 healthy control subjects by a polymerase chain reaction amplification followed by digestion with a restriction endonuclease. We found that the C allele may alter a consensus sequence for the transcription factor NF-kappa B and that its frequency was higher in patients than in control subjects (p =.0085). The genotype distribution also was different, with p =.034 (if C allele dominant, p =.0137, odds ratio 2.037, 95% confidence interval 1.1502-3.6076). The association reported in this study suggests that the GRIN1 gene is a good candidate for the susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 May 119B: 24-7 |
| PMID | 12707933 |
| Title | N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia: TDT and case-control analyses. |
| Abstract | The N-methyl-d-aspartate glutamate receptors (NMDAR) act in the CNS as regulators of the release of neurotransmitters such as dopamine, noradrenaline, acetylcholine, and GABA. It has been suggested that a weakened glutamatergic tone increases the risk of sensory overload and of exaggerated responses in the monoaminergic system, which is consistent with the symptomatology of schizophrenia. We studied two silent polymorphisms in GRIN1. GRIN1/1 is a G/C substitution localized on the 5' untranslated region; GRIN1/10 is an A/G substitution localized in exon 6 of GRIN1. Minor allele frequencies in our sample were calculated to be 0.05 and 0.2 respectively. We genotyped 86 nuclear families and 91 ethnically matched case-control pairs. Both samples were collected from the Toronto area. We tested the hypothesis that GRIN1 polymorphisms were associated with schizophrenia using the transmission disequilibrium test (TDT) and comparing allele frequencies between cases and controls. The results are as follows: GRIN1/1: chi(2) = 2.19, P = 0.14; GRIN1/10: chi(2) = 1.5, P = 0.22. For the case-control sample: GRIN1/1: chi(2) = 0.013, P = 0.908; GRIN1/10: chi(2) = 0.544, P = 0.461. No significant results were obtained. Haplotype analyses showed a borderline significant result for the 2,1 haplotype (chi(2) = 3.86, P-value = 0.049). An analysis of variance (ANOVA) to evaluate the association between genetic makeup and age at onset was performed, with no significant results: GRIN1/1, F[df = 2] = 0.42, P-value = 0.659; GRIN1/10, F[df = 2] = 0.16, P-value = 0.853. We are currently collecting additional samples to increase the power of the analyses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Am J Pharmacogenomics 2005 -1 5: 149-60 |
| PMID | 15952869 |
| Title | Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope. |
| Abstract | No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders. There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions. Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | J. Neurochem. 2005 Jul 94: 324-36 |
| PMID | 15998284 |
| Title | Histone methylation at gene promoters is associated with developmental regulation and region-specific expression of ionotropic and metabotropic glutamate receptors in human brain. |
| Abstract | Glutamatergic signaling is regulated, in part, through differential expression of NMDA and AMPA/KA channel subunits and G protein-coupled metabotropic receptors. In human brain, region-specific expression patterns of glutamate receptor genes are maintained over the course of decades, suggesting a role for molecular mechanisms involved in long-term regulation of transcription, including methylation of lysine residues at histone N-terminal tails. Using a native chromatin immunoprecipitation assay, we studied histone methylation marks at proximal promoters of 16 ionotropic and metabotropic glutamate receptor genes (GRIN1,2A-D; GRIA1,3,4; GRIK2,4,5; GRM1,3,4,6,7 ) in cerebellar cortex collected across a wide age range from midgestation to 90 years old. Levels of di- and trimethylated histone H3-lysine 4, which are associated with open chromatin and transcription, showed significant differences between promoters and a robust correlation with corresponding mRNA levels in immature and mature cerebellar cortex. In contrast, levels of trimethylated H3-lysine 27 and H4-lysine 20, two histone modifications defining silenced or condensed chromatin, did not correlate with transcription but were up-regulated overall in adult cerebellum. Furthermore, differential gene expression patterns in prefrontal and cerebellar cortex were reflected by similar differences in H3-lysine 4 methylation at promoters. Together, these findings suggest that histone lysine methylation at gene promoters is involved in developmental regulation and maintenance of region-specific expression patterns of ionotropic and metabotropic glutamate receptors. The association of a specific epigenetic mark, H3-(methyl)-lysine 4, with the molecular architecture of glutamatergic signaling in human brain has potential implications for schizophrenia and other disorders with altered glutamate receptor function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Eur. J. Hum. Genet. 2005 Jul 13: 807-14 |
| PMID | 15841096 |
| Title | An association study of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B) in schizophrenia with universal DNA microarray. |
| Abstract | Dysfunction of the N-methyl-D-aspartate (NMDA) receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of several antagonists and on observation of genetic animal models. To conduct association analysis of the NMDA receptors in the Chinese population, we examined 16 reported SNPs across the NMDA receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B), five of which were identified in the Chinese population. In this study, we combined universal DNA microarray and ligase detection reaction (LDR) for the purposes of association analysis, an approach we considered to be highly specific as well as offering a potentially high throughput of SNP genotyping. The association study was performed using 253 Chinese patients with schizophrenia and 140 Chinese control subjects. No significant frequency differences were found in the analysis of the alleles but some were found in the haplotypes of the GRIN2B gene. The interactions between the GRIN1 and GRIN2B genes were evaluated using the multifactor-dimensionality reduction (MDR) method, which showed a significant genetic interaction between the G1001C in the GRIN1 gene and the T4197C and T5988C polymorphisms in the GRIN2B gene. These findings suggest that the combined effects of the polymorphisms in the GRIN1 and GRIN2B genes might be involved in the etiology of schizophrenia.European Journal of Human Genetics (2005) 13, 807-814. doi:10.1038/sj.ejhg.5201418 Published online 20 April 2005. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | J. Biomol. Struct. Dyn. 2005 Feb 22: 399-410 |
| PMID | 15588104 |
| Title | Structural consequences of D481N/K483Q mutation at glycine binding site of NMDA ionotropic glutamate receptors: a molecular dynamics study. |
| Abstract | N-Methyl-D-Aspartate (NMDA) receptors are the ligand gated as well as voltage sensitive ionotropic glutamate receptors, widely distributed in the vertebrate central nervous system and they play critical role in the pathogenesis of schizophrenia. Molecular dynamics simulations have been carried out on high resolution crystal structure of NR1 subunit of NMDA receptor ligand binding core (S1S2) in four different conformations. We have investigated consequence of D481N/K483Q double mutation of NR1 subunit from simulation results of (a) glycine bound form (WG), (b) unbound (closed-apo) form (WOG), (c) a double mutated form (DM), and (d) the antagonist (5,7-dichlorokynuric acid) bound form (DCKA). The MD simulations and simulated annealing for 4ns show a distinct conformation for the double mutated conformation that neither follows the antagonist nor apo conformation. There are two distinct sites, loop1 and loop2 where the double mutated structure in its glycine bound form shows significant RMSD deviations as compared to the wild-type. The interactions of glycine with the receptor remain theoretically unchanged in the double mutated structure and there is no detachment of S1S2 domains. The results suggest that separation of S1 and S2 domains may not be essential for channel inactivation. Therefore, it is hypothesized that hypoactivation of NMDA receptor channels may arise out of the conformational changes at non-conserved Loop1 and Loop2 regions observed in the mutated structure. The Loop1 and Loop2 regions responsible for inter-subunit interactions in a functional NMDA receptor, may therefore, render the ligand bound form defunct. This may account for behavioral anomalies due to receptor inactivation seen in GRIN1 mutated mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Psychiatr. Genet. 2006 Oct 16: 183-4 |
| PMID | 16969270 |
| Title | No association between genetic variants at the GRIN1 gene and bipolar disorder in a German sample. |
| Abstract | Disturbed glutamatergic neurotransmission has been implicated in the pathogenesis of schizophrenia and bipolar disorder, with the N-methy-D-aspartate receptors being in the focus of research. The NR1 subunit, which is encoded by the gene GRIN1, plays a key role in the functionality of N-methy-D-aspartate receptors. We tested the association between GRIN1 and bipolar disorder in a sample of German descent, consisting of 306 bipolar disorder patients and 319 population-based controls. No significant association was found. In accordance with our recent findings, we hypothesized that restricting case definition to individuals with a history of persecutory delusions might clarify the relationship between bipolar disorder and GRIN1. This stratified analysis did not yield any significant association either. Our results do not support an association of the GRIN1 gene with bipolar disorder in the German population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Biol. Psychiatry 2006 Apr 59: 747-53 |
| PMID | 16476413 |
| Title | Significant association between the genetic variations in the 5' end of the N-methyl-D-aspartate receptor subunit gene GRIN1 and schizophrenia. |
| Abstract | N-methyl-D-aspartate (NMDA) receptors play important roles in many neurophysiological processes. Evidence from previous studies indicate that NMDA receptors contribute to the pathophysiology of schizophrenia. Two NMDA receptor subunit genes, GRIN1 and GRIN2A, are both good candidate genes for schizophrenia. We genotyped five single nucleotide polymorphisms (SNPs) in GRIN1 and two in GRIN2A in 2455 Han Chinese subjects, including population- and family-based samples, and performed case-control and transmission disequilibrium test (TDT) analyses. A microsatellite in GRIN2A was genotyped in population-based samples and a Mann-Whitney U test was performed. A highly significant association was detected at the 5' end of GRIN1. Analyses of single variants and multiple-locus haplotypes indicate that the association is mainly generated by rs11146020 (case-control study: p = .0000013, odds ratio = .61, 95% confidence interval .50-.74; TDT: p = .0019, T/NT = 79/123). No association was found in the GRIN2A polymorphisms. Our results provide support for the hypothesis that NMDA receptors are an important factor in schizophrenia. Moreover, rs11146020 is located in 5' untranslated region where several functional elements have been found. Hence, the SNP is a potential candidate in altering risk for schizophrenia and worthy of further replication and functional study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | 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 |
| 19 | 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 |
| 20 | 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 |
| 21 | Schizophr. Res. 2007 Dec 97: 277-88 |
| PMID | 17942280 |
| Title | Elevated GRIA1 mRNA expression in Layer II/III and V pyramidal cells of the DLPFC in schizophrenia. |
| Abstract | The functional integrity of the dorsolateral prefrontal cortex (DLPFC) is altered in schizophrenia leading to profound deficits in working memory and cognition. Growing evidence indicates that dysregulation of glutamate signaling may be a significant contributor to the pathophysiology mediating these effects; however, the contribution of NMDA and AMPA receptors in the mediation of this deficit remains unclear. The equivocality of data regarding ionotropic glutamate receptor alterations of subunit expression in the DLPFC of schizophrenics is likely reflective of subtle alterations in the cellular and molecular composition of specific neuronal populations within the region. Given previous evidence of Layer II/III and V pyramidal cell alterations in schizophrenia and the significant influence of subunit composition on NMDA and AMPA receptor function, laser capture microdissection combined with quantitative PCR was used to examine the expression of AMPA (GRIA1-4) and NMDA (GRIN1, 2A and 2B) subunit mRNA levels in Layer II/III and Layer V pyramidal cells in the DLPFC. Comparisons were made between individuals diagnosed with schizophrenia, bipolar disorder, major depressive disorder and controls (n=15/group). All subunits were expressed at detectable levels in both cell populations for all diseases as well as for the control group. Interestingly, GRIA1 mRNA was significantly increased in both cell types in the schizophrenia group compare to controls, while similar trends were observed in major depressive disorder (Layers II/III and V) and bipolar disorder (Layer V). These data suggest that increased GRIA1 subunit expression may contribute to schizophrenia pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Schizophr. Res. 2007 Dec 97: 277-88 |
| PMID | 17942280 |
| Title | Elevated GRIA1 mRNA expression in Layer II/III and V pyramidal cells of the DLPFC in schizophrenia. |
| Abstract | The functional integrity of the dorsolateral prefrontal cortex (DLPFC) is altered in schizophrenia leading to profound deficits in working memory and cognition. Growing evidence indicates that dysregulation of glutamate signaling may be a significant contributor to the pathophysiology mediating these effects; however, the contribution of NMDA and AMPA receptors in the mediation of this deficit remains unclear. The equivocality of data regarding ionotropic glutamate receptor alterations of subunit expression in the DLPFC of schizophrenics is likely reflective of subtle alterations in the cellular and molecular composition of specific neuronal populations within the region. Given previous evidence of Layer II/III and V pyramidal cell alterations in schizophrenia and the significant influence of subunit composition on NMDA and AMPA receptor function, laser capture microdissection combined with quantitative PCR was used to examine the expression of AMPA (GRIA1-4) and NMDA (GRIN1, 2A and 2B) subunit mRNA levels in Layer II/III and Layer V pyramidal cells in the DLPFC. Comparisons were made between individuals diagnosed with schizophrenia, bipolar disorder, major depressive disorder and controls (n=15/group). All subunits were expressed at detectable levels in both cell populations for all diseases as well as for the control group. Interestingly, GRIA1 mRNA was significantly increased in both cell types in the schizophrenia group compare to controls, while similar trends were observed in major depressive disorder (Layers II/III and V) and bipolar disorder (Layer V). These data suggest that increased GRIA1 subunit expression may contribute to schizophrenia pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Psychiatr. Genet. 2007 Oct 17: 308-10 |
| PMID | 17728671 |
| Title | Possible association between genetic variants at the GRIN1 gene and schizophrenia with lifetime history of depressive symptoms in a German sample. |
| Abstract | Genetic variation in glutamatergic signalling pathways is believed to play a substantial role in the aetiology of schizophrenia. The N-methyl-D-aspartate receptor subunit gene GRIN1 has been proposed as a candidate gene for schizophrenia. We tested for a potential association between schizophrenia and four single nucleotide polymorphisms (rs4880213, rs11146020, rs6293, and rs10747050) and one microsatellite marker at GRIN1 in a German sample of 354 patients and 323 controls. We found significant associations in single-marker and haplotype-based analyses (P<0.05). Significance was more pronounced (P<0.01) in the subset of patients with a lifetime history of major depression, a subgroup of schizophrenia described previously as a promising phenotypic subtype in genetic studies of schizophrenia. Although significances did not withstand correction for multiple testing, the results of our exploratory analysis warrant further studies on GRIN1 and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Fa Yi Xue Za Zhi 2008 Oct 24: 369-74, 377 |
| PMID | 18979923 |
| Title | [The association between glutamate receptor gene SNP and schizophrenia]. |
| Abstract | Glutamate is a necessary excitatory neurotransmitter in human nervous system, which runs a biological function by binding with corresponding receptors. Psychiatric diseases occur when genes which encode receptors become dysfunctional. The authors have reviewed related literature and summarized the association between schizophrenia and glutamate receptor gene SNPs such as rs11146020 in GRIN1, 366C/G in GRIN2B, and rs1468412 in GRM3, etc. Due to controversial results in various studies, it is hypothesized that schizophrenia are complicated polygenic inherited diseases. Some sites such as 366C/G, 2664C/T and rs1408766 (C/T) possess with valuable genetic polymorphisms and might potentially contribute to personal identification and paternity testing. Studies in this field may have a potential significance in forensic psychiatry practice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Psychopharmacology (Berl.) 2008 Oct 200: 217-30 |
| PMID | 18597079 |
| Title | Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. |
| Abstract | schizophrenic patients demonstrate prominent negative and cognitive symptoms that are poorly responsive to antipsychotic treatment. Abnormal glutamatergic neurotransmission may contribute to these pathophysiological dimensions of schizophrenia. We examined the involvement of the glycine coagonist site on the N-methyl-D: -aspartate receptor (NMDAR) glycine coagonist site in the modulation of negative and cognitive endophenotypes in mice. Behavioral phenotypes relevant to schizophrenia were assessed in GRIN1(D481N) mice that have reduced NMDAR glycine affinity. GRIN1(D481N) mutant mice showed abnormally persistent latent inhibition (LI) that was reversed by two agents that enhance NMDAR glycine site function, D: -serine (600 mg/kg) and ALX-5407 (1 mg/kg), and by the classical atypical antipsychotic clozapine (3 mg/kg). Similarly, blockade of the NMDAR glycine site with the antagonist L-701,324 (5 mg/kg) induced persistent LI in C57BL6/J mice. In a social affiliations task, GRIN1(D481N) mutant animals showed reduced social approach behaviors that were normalized by D: -serine (600 mg/kg). During a nonassociative spatial object recognition task, mutant mice demonstrated impaired reactivity to a spatial change that was reversible by D: -serine (300 and 600 mg/kg) and clozapine (0.75 mg/kg). In contrast, responses to social novelty and nonspatial change remained unaffected, indicating that the GRIN1(D481N) mutation induces selective deficits in sociability and spatial discrimination, while leaving intact the ability to react to novelty. Genetic and pharmacologically induced deficiencies in glycine binding appear to model the impairments in behavioral flexibility, sociability, and spatial recognition related to the negative and cognitive symptoms of schizophrenia. Antipsychotics that target the NMDAR glycine site may be beneficial in treating such psychiatric symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | Psychopharmacology (Berl.) 2008 Oct 200: 217-30 |
| PMID | 18597079 |
| Title | Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. |
| Abstract | schizophrenic patients demonstrate prominent negative and cognitive symptoms that are poorly responsive to antipsychotic treatment. Abnormal glutamatergic neurotransmission may contribute to these pathophysiological dimensions of schizophrenia. We examined the involvement of the glycine coagonist site on the N-methyl-D: -aspartate receptor (NMDAR) glycine coagonist site in the modulation of negative and cognitive endophenotypes in mice. Behavioral phenotypes relevant to schizophrenia were assessed in GRIN1(D481N) mice that have reduced NMDAR glycine affinity. GRIN1(D481N) mutant mice showed abnormally persistent latent inhibition (LI) that was reversed by two agents that enhance NMDAR glycine site function, D: -serine (600 mg/kg) and ALX-5407 (1 mg/kg), and by the classical atypical antipsychotic clozapine (3 mg/kg). Similarly, blockade of the NMDAR glycine site with the antagonist L-701,324 (5 mg/kg) induced persistent LI in C57BL6/J mice. In a social affiliations task, GRIN1(D481N) mutant animals showed reduced social approach behaviors that were normalized by D: -serine (600 mg/kg). During a nonassociative spatial object recognition task, mutant mice demonstrated impaired reactivity to a spatial change that was reversible by D: -serine (300 and 600 mg/kg) and clozapine (0.75 mg/kg). In contrast, responses to social novelty and nonspatial change remained unaffected, indicating that the GRIN1(D481N) mutation induces selective deficits in sociability and spatial discrimination, while leaving intact the ability to react to novelty. Genetic and pharmacologically induced deficiencies in glycine binding appear to model the impairments in behavioral flexibility, sociability, and spatial recognition related to the negative and cognitive symptoms of schizophrenia. Antipsychotics that target the NMDAR glycine site may be beneficial in treating such psychiatric symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Pharmacol. Biochem. Behav. 2009 Feb 91: 610-20 |
| PMID | 18940194 |
| Title | Mutant mice with reduced NMDA-NR1 glycine affinity or lack of D-amino acid oxidase function exhibit altered anxiety-like behaviors. |
| Abstract | Several compounds that promote activation of the N-methyl-d-aspartate receptor (NMDAR) glycine site have been proposed as treatments for schizophrenia, but the impact of these putative antipsychotics on anxiety remains unclear. In this study, we employed genetic and pharmacological mouse models of altered NMDAR glycine site function to examine the effects of these proposed treatments in unconditioned tests of anxiety. In the elevated plus-maze, open field, and novel object test, homozygous GRIN1(D481N) mutant mice that have a five-fold reduction in NMDAR glycine affinity demonstrated an anxiolytic-like phenotype. In contrast, d-serine, a direct activator of the NMDAR glycine site, and ALX-5407, a glycine transporter-1 (GlyT-1) inhibitor, enhanced anxiety-like behaviors in wild-type and GRIN1(D481N) mutant animals. Homozygous Dao1(G181R) mutant mice that lack function of the d-serine catabolic enzyme, d-amino acid oxidase (DAO), displayed an elevation in anxiety. Deficient DAO activity also reversed the anxiolytic effects of diminished NMDAR function in mice carrying both the homozygous GRIN1(D481N) and Dao1(G181R) mutation. Thus, a direct agonist of the NMDAR glycine site, a GlyT-1 inhibitor, and suppression of DAO function induced anxiogenic-like behaviors. Consequently, application of these treatments for amelioration of schizophrenic symptoms necessitates caution as an enhancement of comorbid anxiety disorders may result. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Pharmacol. Biochem. Behav. 2009 Feb 91: 610-20 |
| PMID | 18940194 |
| Title | Mutant mice with reduced NMDA-NR1 glycine affinity or lack of D-amino acid oxidase function exhibit altered anxiety-like behaviors. |
| Abstract | Several compounds that promote activation of the N-methyl-d-aspartate receptor (NMDAR) glycine site have been proposed as treatments for schizophrenia, but the impact of these putative antipsychotics on anxiety remains unclear. In this study, we employed genetic and pharmacological mouse models of altered NMDAR glycine site function to examine the effects of these proposed treatments in unconditioned tests of anxiety. In the elevated plus-maze, open field, and novel object test, homozygous GRIN1(D481N) mutant mice that have a five-fold reduction in NMDAR glycine affinity demonstrated an anxiolytic-like phenotype. In contrast, d-serine, a direct activator of the NMDAR glycine site, and ALX-5407, a glycine transporter-1 (GlyT-1) inhibitor, enhanced anxiety-like behaviors in wild-type and GRIN1(D481N) mutant animals. Homozygous Dao1(G181R) mutant mice that lack function of the d-serine catabolic enzyme, d-amino acid oxidase (DAO), displayed an elevation in anxiety. Deficient DAO activity also reversed the anxiolytic effects of diminished NMDAR function in mice carrying both the homozygous GRIN1(D481N) and Dao1(G181R) mutation. Thus, a direct agonist of the NMDAR glycine site, a GlyT-1 inhibitor, and suppression of DAO function induced anxiogenic-like behaviors. Consequently, application of these treatments for amelioration of schizophrenic symptoms necessitates caution as an enhancement of comorbid anxiety disorders may result. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | J. Mol. Neurosci. 2009 Jun 38: 178-81 |
| PMID | 18792810 |
| Title | Association between the G1001C polymorphism in the GRIN1 gene promoter and schizophrenia in the Iranian population. |
| Abstract | schizophrenia is a complex genetic disorder to which genetic variation in the glutamatergic signaling pathways is believed to play a substantial role in the etiology of the disease. Association studies have implicated the N-methyl-D-aspartate receptor subunit gene, GRIN1, as a candidate gene for schizophrenia. In this report, we used a case control study to establish the possible association between the G1001C polymorphism in the GRIN1 gene promoter region and schizophrenia in an Iranian cohort of 200 unrelated patients and 200 controls. The allelic and genotypic frequencies of the polymorphism were determined using polymerase chain reaction restriction fragment length polymorphism. Data analysis using logistic regression and the Mantel-Haenszel chi-square test revealed a strong association between the G1001C polymorphism and schizophrenia (CG genotype: odds ratio (OR) = 2.12, 95% confidence interval (CI) 1.34-3.48, P = 0.001 and CC genotype: OR = 29.10, 95% CI 3.40-565.78, P < 0.001). Furthermore, the C allele is significantly associated with an increasing risk of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Neurosci Biobehav Rev 2010 May 34: 958-77 |
| PMID | 20060416 |
| Title | Genetic association studies of glutamate, GABA and related genes in schizophrenia and bipolar disorder: a decade of advance. |
| Abstract | schizophrenia (SZ) and bipolar disorder (BD) are debilitating neurobehavioural disorders likely influenced by genetic and non-genetic factors and which can be seen as complex disorders of synaptic neurotransmission. The glutamatergic and GABAergic neurotransmission systems have been implicated in both diseases and we have reviewed extensive literature over a decade for evidence to support the association of glutamate and GABA genes in SZ and BD. Candidate-gene based population and family association studies have implicated some ionotrophic glutamate receptor genes (GRIN1, GRIN2A, GRIN2B and GRIK3), metabotropic glutamate receptor genes (such as GRM3), the G72/G30 locus and GABAergic genes (e.g. GAD1 and GABRB2) in both illnesses to varying degrees, but further replication studies are needed to validate these results. There is at present no consensus on specific single nucleotide polymorphisms or haplotypes associated with the particular candidate gene loci in these illnesses. The genetic architecture of glutamate systems in bipolar disorder need to be better studied in view of recent data suggesting an overlap in the genetic aetiology of SZ and BD. There is a pressing need to integrate research platforms in genomics, epistatic models, proteomics, metabolomics, neuroimaging technology and translational studies in order to allow a more integrated understanding of glutamate and GABAergic signalling processes and aberrations in SZ and BD as well as their relationships with clinical presentations and treatment progress over time. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Neurosci. Lett. 2010 Jul 478: 61-5 |
| PMID | 20438806 |
| Title | Association analysis of GRIN1 and GRIN2B polymorphisms and Parkinson's disease in a hospital-based case-control study. |
| Abstract | Hyperactivation of N-methyl-d-aspartate receptors (NMDARs) leads to neuronal excitotoxicity and is suggested to play a role in many brain disorders, including Alzheimer's disease and schizophrenia. However, the association between polymorphisms in the genes that code for NMDAR subunits, N-methyl-d-aspartate 1 and 2B (GRIN1 and GRIN2B) and Parkinson's disease (PD) remains unclear. In a hospital-based case-control study of PD, DNA samples were collected from 101 PD patients and 205 healthy controls. Genotyping assays were used to screen for polymorphisms in the GRIN1 (rs2301364 T>C, rs28489906 T>C, and rs4880213 T>C) and GRIN2B (C366G, C2664T, and rs1805476 T>G) genes, and logistic regression analysis was then used to assess the association between these single nucleotide polymorphisms (SNPs) and PD susceptibility. None of the 6 SNPs were significantly associated with PD risk on their own. However, in conjunction with putative low-risk genotypes for the GRIN1 gene, the GRIN2BC366G variant was significantly associated with reduced PD risk compared with the homozygous genotype 366CC (OR=0.38, 95%CI=0.17-0.93, P=0.033). A synergistic effect on risk reduction was observed in subjects who carried multiple polymorphisms of GRIN1 and the GRIN2BC366G polymorphism (OR=0.78, 95%CI=0.59-1.02, P(trend)=0.073). Our results suggest that polymorphisms in the GRIN1 and GRIN2B genes may serve as potential biomarkers for a reduced risk of PD among the Chinese population in Taiwan. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2011 Nov 879: 3169-83 |
| PMID | 21992750 |
| Title | Analysis of free D-serine in mammals and its biological relevance. |
| Abstract | D-Serine is a unique endogenous substance enriched in the brain at the exceptionally high concentrations as a free D-amino acid in mammals throughout their life. Peripheral tissues and blood contain low or trace levels of the D-amino acid. In the nervous systems, D-serine appears to act as an intrinsic coagonist for the N-methyl-D-aspartate type glutamate receptor (NMDA receptor) based upon the following characteristics: (i) D-serine stereoselectively binds to and stimulates the glycine-regulatory site of the NMDA receptor consisting of GRIN1/GRIN2 subunits more potently than glycine with an affinity and ED50 at high nanomolar ranges, (ii) the selective elimination of D-serine in brain tissues attenuates the NMDA receptor functions, indicating an indispensable role in physiological activation of the glutamate receptor, and (iii) the distribution of D-serine is uneven and closely correlated with that of the binding densities of the various NMDA receptor sites, and especially of the GRIN2B subunit in the brain. Moreover, d-serine exerts substantial influence on the GRIN1/GRIN3-NMDA and ?2 glutamate receptor. In the brain and retina, metabolic processes of D-serine, such as biosynthesis, extracellular release, uptake, and degradation, are observed and some candidate molecules that mediate these processes have been isolated. The fact that the mode of extracellular release of D-serine in the brain differs from that of classical neurotransmitters is likely to be related to the detection of D-serine in both glial cells and neurons, suggesting that d-serine signals could be required for the glia-synapse interaction. Moreover, the findings from the basic experiments and clinical observations support the views that the signaling system of endogenous free D-serine plays important roles, at least, through the action on the NMDA receptors in the brain wiring development and the regulation of higher brain functions, including cognitive, emotional and sensorimotor function. Based upon these data, aberrant D-serine-NMDA receptor interactions have been considered to be involved in the pathophysiology of a variety of neuropsychiatric disorders including schizophrenia and ischemic neuronal cell death. The molecular and cellular mechanisms for regulating the D-serine signals in the nervous system are, therefore, suitable targets for studies aiming to elucidate the causes of neuropsychiatric disorders and for the development of new treatments for intractable neuropsychiatric symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Dec 156B: 913-22 |
| PMID | 21919190 |
| Title | Association of GRIN1 and GRIN2A-D with schizophrenia and genetic interaction with maternal herpes simplex virus-2 infection affecting disease risk. |
| Abstract | N-methyl-D-aspartate (NMDA) receptors are very important for proper brain development and several lines of evidence support that hypofunction of the NMDA receptors are involved in the pathophysiology of schizophrenia. Gene variation and gene-environmental interactions involving the genes encoding the NMDA receptors are therefore likely to influence the risk of schizophrenia. The aim of this study was to determine (1) whether SNP variation in the genes (GRIN1, GRIN2A, GRIN2B, GRIN2C, and GRIN2D) encoding the NMDA receptor were associated with schizophrenia; (2) whether GRIN gene variation in the offspring interacted with maternal herpes simplex virus-2 (HSV-2) seropositivity during pregnancy influencing the risk of schizophrenia later in life. Individuals from three independently collected Danish case control samples were genotyped for 81 tagSNPs (in total 984 individuals diagnosed with schizophrenia and 1,500 control persons) and antibodies against maternal HSV-2 infection were measured in one of the samples (365 cases and 365 controls). Nine SNPs out of 30 in GRIN2B were significantly associated with schizophrenia. One SNP remained significant after Bonferroni correction (rs1806194, P(nominal) ?= 0.0008). Significant interaction between maternal HSV-2 seropositivity and GRIN2B genetic variation in the offspring were observed for seven SNPs and two remained significant after Bonferroni correction (rs1805539, P(nominal) ?= 0.0001 and rs1806205, P(nominal) ?= 0.0008). The significant associations and interactions were located at the 3' region of GRIN2B suggesting that genetic variation in this part of the gene may be involved in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | Transl Psychiatry 2011 -1 1: e55 |
| PMID | 22833210 |
| Title | Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. |
| Abstract | Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Dev. Neurosci. 2012 -1 34: 159-73 |
| PMID | 22571986 |
| Title | Preweaning sensorimotor deficits and adolescent hypersociability in Grin1 knockdown mice. |
| Abstract | Mice with knockdown of the N-methyl-D-aspartate (NMDA) receptor NR1 subunit, encoded by the gene GRIN1, have been investigated as a model for the intrinsic NMDA hypofunction hypothesized for schizophrenia. Previous work has shown that adult GRIN1 mutant mice have overt deficits in habituation and sensorimotor gating, exaggerated reactivity to environmental stimuli, reduced social approach, and other alterations that reflect behavioral manifestations of schizophrenia. In humans, the emergence of overt symptoms of the disorder typically occurs in adolescence or early adulthood, suggesting a role for aberrant maturation of NMDA receptor signaling in symptom onset. The following study evaluated GRIN1 mutant mice for abnormal behavioral phenotypes during the preweaning, adolescent, and adult periods. Measures included open field activity, prepulse inhibition of acoustic startle responses, and social preference in a three-chamber choice task. Mice from the C57BL/6J inbred strain, one of the parental strains for the GRIN1 line, were also tested. The results showed that developmental reduction of NMDA receptor function led to significant alterations in behavior during the second and third weeks of life, including exaggerated startle responses and sensorimotor gating deficits on postnatal day 13, and pronounced hypersociability in adolescence. Male GRIN1 mutant mice were more susceptible than female mice to the detrimental effects of decreased NMDA signaling. Overall, these findings provide evidence that reduced GRIN1 function leads to abnormal phenotypes in the preweaning period, and that deficient NMDA signaling can lead to both overt hypersociability or marked asociality, dependent upon sex and age. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | Neuroscience 2013 May 237: 255-67 |
| PMID | 23396086 |
| Title | Rhythmic theta and delta activity of cortical and hippocampal neuronal networks in genetically or pharmacologically induced N-methyl-D-aspartate receptor hypofunction under urethane anesthesia. |
| Abstract | N-Methyl-d-aspartate receptor (NMDAR) antagonists mimic several symptoms of schizophrenia in healthy subjects, and are used in preclinical disease models. In the present study, the impact of pharmacologically and genetically induced NMDAR hypofunction was assessed in rats and mice, including the NMDAR hypomorphic (GRIN1) mice, with respect to neuronal network oscillations. Field potentials were recorded from the ventro-medial prefrontal cortex (mPFC) and hippocampus (CA1) in rats, as well as spontaneous and elicited hippocampal theta oscillations in response to brainstem stimulation in GRIN1 and wild-type (WT) mice under anesthesia. Effects of the ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor positive allosteric modulator LY451395 were tested in GRIN1 mice and in WT mice following an MK-801 challenge. Recordings from the mPFC and CA1 in rats revealed regular delta and theta oscillations, respectively, which were disrupted by MK-801. In WT mice, MK-801 reduced both spontaneous and elicited hippocampal theta power. Age-matched GRIN1 mice showed abnormal hippocampal field potentials, resembling activity seen after administration of MK-801 in WT mice, but also epileptiform discharges. Administration of MK-801 achieved high levels of NMDAR occupancy (84-98%) in both rats and mice, which is comparable to the approximately 90-95% reduction of NMDAR expression in the GRIN1 mouse. Impaired elicited CA1 theta oscillation in WT mice following MK-801, or GRIN1 mice was significantly improved by LY451395. These findings demonstrate similar, although not identical, changes in network activity following reduction in functioning NMDARs induced by acute pharmacological or genetic manipulations, indicating that these novel neurophysiological models could be used in evaluating drug candidates targeting glutamate neurotransmission. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | Neurosci. Lett. 2013 Sep 551: 58-61 |
| PMID | 23880023 |
| Title | Genetic variation of GRIN1 confers vulnerability to methamphetamine-dependent psychosis in a Thai population. |
| Abstract | GRIN1 is a gene that encodes the N-methyl-d aspartate (NMDA) receptor subunit1 (NR1). Variations of GRIN1 have been identified as a risk factor for schizophrenia and drug dependence, supporting hypotheses of glutamatergic dysfunction in these disorders. Methamphetamine (METH) is a psychostimulant drug which can induce psychotic symptoms reminiscent of those found in schizophrenia; thus GRIN1 is a candidate gene for vulnerability to METH dependence or METH-dependent psychosis. The present study examined two polymorphisms of GRIN1, rs11146020 (G1001C) and rs1126442 (G2108A), in 100 male Thai METH-dependent patients and 103 healthy controls using PCR-RFLP techniques. Neither polymorphism was significantly associated with METH dependence, although rs1126442 was highly significantly associated with METH-dependent psychosis, in which the A allele showed reduced frequency (P<0.00001). The present findings indicate that the rs1126442 of GRIN1 contributes to the genetic vulnerability to psychosis in METH-dependent subjects in the Thai population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | Fa Yi Xue Za Zhi 2013 Apr 29: 107-9 |
| PMID | 23930503 |
| Title | [Correlation between genetic polymorphisms of -855 G/C and -1140 G/A in GRIN1 gene and paranoid schizophrenia]. |
| Abstract | To investigate the single nucleotide polymorphisms (SNP) of -855 G/C and -1140 G/A in promoter regions of GRIN1 gene and find their genetic correlation to paranoid schizophrenia as well as their applicable values in forensic medicine. The genetic polymorphisms of -855 G/C and -1140 G/A at the 5' end of GRIN1 gene were detected by PCR restriction fragment length polymorphism and PAGE in 183 healthy unrelated individuals of northern Chinese Han population and 172 patients of paranoid schizophrenia, respectively. The chi2 test was used to identify Hardy-Weinberg equilibrium of the genotype distribution. The differences of genotypes and allelic frequency distributions were compared between the two groups. Distributions of the genotypic frequencies satisfied Hardy-Weinberg equilibrium in both groups. The difference of genotypes was statistically significant between female patient group and female control group in -855 G/C distribution (P < 0.05). The differences of genotypes and allelic frequencies were statistically significant not only between the patient group and the control group but also between female patient group and female control group in -1140 G/A distribution (P < 0.05). The SNP of -1140 G/A in promoter regions of GRIN1 gene might positively correlate to paranoid schizophrenia. The genetic factor of schizophrenia is involved in gender tendency. And it could be useful in forensic identification of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | Behav. Brain Res. 2013 Sep 252: 405-14 |
| PMID | 23806621 |
| Title | Pharmacological disruption of mouse social approach behavior: relevance to negative symptoms of schizophrenia. |
| Abstract | Social withdrawal is one of several negative symptoms of schizophrenia, all of which are poorly treated by current therapies. One challenge in developing agents with efficacy against negative symptoms is the lack of suitable preclinical models. The social approach test was used as the basis for developing an assay to test emerging therapies for negative symptoms. NMDA antagonists and dopamine agonists have been used extensively to produce or disrupt behaviors thought to be rodent correlates of positive and cognitive symptoms of schizophrenia. The aim of these studies was to determine whether sociability of mice in the 3-chamber social approach test could be disrupted and whether this paradigm could have utility in predicting efficacy against negative symptoms. The criteria for such a model were: a lack of response to antipsychotics and attenuation by agents such as the glycine agonist, d-cycloserine, which has been shown to possess clinical efficacy against negative symptoms. Administration of the NMDA antagonists MK-801, PCP, or ketamine did not disrupt sociability. In contrast, GRIN1 hypomorph mice displayed a social deficit which was not reversed by atypical antipsychotics or d-serine. d-Amphetamine disrupted sociability without stimulating locomotor activity and its effect was not reversed by antipsychotics. The GABAA inverse agonist, FG-7142, reduced sociability and this was reversed by the GABAA antagonist, flumazenil and dcycloserine, but not by clozapine, or the GABAA benzodiazepine anxiolytic, alprazolam. Based on our criteria, the GABAA model warrants further evaluation to confirm that this paradigm has utility as a preclinical model for predicting efficacy against negative symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | BMC Res Notes 2013 -1 6: 203 |
| PMID | 23688147 |
| Title | ENU-mutagenesis mice with a non-synonymous mutation in Grin1 exhibit abnormal anxiety-like behaviors, impaired fear memory, and decreased acoustic startle response. |
| Abstract | The GRIN1 (glutamate receptor, ionotropic, NMDA1) gene expresses a subunit of N-methyl-D-aspartate (NMDA) receptors that is considered to play an important role in excitatory neurotransmission, synaptic plasticity, and brain development. GRIN1 is a candidate susceptibility gene for neuropsychiatric disorders, including schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD). In our previous study, we examined an N-ethyl-N-nitrosourea (ENU)-generated mutant mouse strain (GRIN1(Rgsc174)/GRIN1+) that has a non-synonymous mutation in GRIN1. These mutant mice showed hyperactivity, increased novelty-seeking to objects, and abnormal social interactions. Therefore, GRIN1(Rgsc174)/GRIN1+ mice may serve as a potential animal model of neuropsychiatric disorders. However, other behavioral characteristics related to these disorders, such as working memory function and sensorimotor gating, have not been fully explored in these mutant mice. In this study, to further investigate the behavioral phenotypes of GRIN1(Rgsc174)/GRIN1+ mice, we subjected them to a comprehensive battery of behavioral tests. There was no significant difference in nociception between GRIN1(Rgsc174)/GRIN1+ and wild-type mice. The mutants did not display any abnormalities in the Porsolt forced swim and tail suspension tests. We confirmed the previous observations that the locomotor activity of these mutant mice increased in the open field and home cage activity tests. They displayed abnormal anxiety-like behaviors in the light/dark transition and the elevated plus maze tests. Both contextual and cued fear memory were severely deficient in the fear conditioning test. The mutant mice exhibited slightly impaired working memory in the eight-arm radial maze test. The startle amplitude was markedly decreased in GRIN1(Rgsc174)/GRIN1+ mice, whereas no significant differences between genotypes were detected in the prepulse inhibition (PPI) test. The mutant mice showed no obvious deficits in social behaviors in three different social interaction tests. This study demonstrated that the GRIN1(Rgsc174)/GRIN1+ mutation causes abnormal anxiety-like behaviors, a deficiency in fear memory, and a decreased startle amplitude in mice. Although GRIN1(Rgsc174)/GRIN1+ mice only partially recapitulate symptoms of patients with ADHD, schizophrenia, and bipolar disorder, they may serve as a unique animal model of a certain subpopulation of patients with these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Psychiatry Res 2014 Aug 218: 356-8 |
| PMID | 24814139 |
| Title | A recently-discovered NMDA receptor gene, GRIN3B, is associated with duration mismatch negativity. |
| Abstract | The study explored associations between mismatch negativity and N-methyl-d-aspartic acid receptor subunit genes, GRIN1, GRIN2B and GRIN3B in healthy subjects and schizophrenia. Nineteen single-nucleotide polymorphisms were genotyped in 138 schizophrenia patients and 103 healthy subjects. Rs2240158 of GRIN3B was significantly associated with mismatch negativity in healthy subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Genes Brain Behav. 2014 Nov 13: 850-62 |
| PMID | 25327402 |
| Title | NMDA receptor-deficient mice display sexual dimorphism in the onset and severity of behavioural abnormalities. |
| Abstract | N-methyl-d-aspartate (NMDA) receptor-deficient mice can be used to understand the role that NMDA receptors (NMDARs) play in the pathophysiology of neurodevelopmental disorders such as schizophrenia. Genetically modified mice with low levels of NR1 subunit (NR1 knockdown mice) have reduced receptor levels throughout development, and have robust abnormalities in behaviours that are relevant to schizophrenia. We traced the onset and severity of these behaviours at three developmental stages to understand when in development the underlying circuits depend on intact NMDAR function. We examined social behaviour, working memory, executive function, locomotor activity and stereotypy at 3, 6 and 12?weeks of age in NR1 knockdown mice and their wild-type littermates. We discovered that each of these behaviours had a unique developmental trajectory in mutant mice, and males showed an earlier onset and severity than females in several behaviours. Hyperlocomotion was most substantial in juvenile mice and plateaued in adult mice, whereas stereotypy progressively worsened with age. Impairments in working memory and sociability were sexually dimorphic, with deficits first detected in peri-adolescent males but only detected in adult females. Interestingly, executive function was most impaired in peri-adolescent mice of either sex. Furthermore, while juvenile mutant mice had some ability to problem solve in the puzzle box test, the same mice lost this ability when tested 4?weeks later. Our studies highlight key developmental periods for males and females in the expression of behaviours that are relevant to psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | Psychiatry Res 2015 Oct 229: 690-4 |
| PMID | 26296755 |
| Title | Low expression of Gria1 and Grin1 glutamate receptors in the nucleus accumbens of Spontaneously Hypertensive Rats (SHR). |
| Abstract | The Spontaneously Hypertensive Rat (SHR) strain is a classical animal model for the study of essential hypertension. Recently, our group suggested that this strain could be a useful animal model for schizophrenia, which is a severe mental illness with involvement of glutamatergic system. The aim of this study is to investigate glutamatergic receptors (Gria1 and GRIN1) and glycine transporter (Glyt1) gene expression in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) of SHR animals. The effects in gene expression of a chronic treatment with antipsychotic drugs (risperidone, haloperidol and clozapine) were also analyzed. Animals were treated daily for 30 days, and euthanized for brain tissue collection. The expression pattern was evaluated by Real Time Reverse-Transcriptase (RT) PCR technique. In comparison to control rats, SHR animals present a lower expression of both NMDA (GRIN1) and AMPA (Gria1) gene receptors in the NAcc. Antipsychotic treatments were not able to change gene expressions in any of the regions evaluated. These findings provide evidence for the role of glutamatergic changes in schizophrenia-like phenotype of the SHR strain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Psychiatr. Genet. 2015 Jun 25: 135-6 |
| PMID | 25714447 |
| Title | Association of GRIN1, ABCB1, and DRD4 genes and response to antipsychotic drug treatment in schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | Acta Neuropsychiatr 2015 Dec 27: 375-9 |
| PMID | 26028254 |
| Title | A 16-year-old girl with anti-NMDA-receptor encephalitis and family history of psychotic disorders. |
| Abstract | Autoimmune NMDA-R encephalitis (ANRE) shares clinical features with schizophrenia. Recent research also indicates that both disorders are associated with dysfunction of the N-Methyl-D-Aspartate glutamate receptors (NMDA-R) subunit 1. We present the case of Ms A, 16 years old. Ms A presented with acute personality change, bizarre behaviour, delusional ideas and atypical seizures. She had a family history of psychotic disorders, and autistic traits diagnosed in childhood. She was initially diagnosed with a psychotic disorder. Delayed testing of CSF indicated ANRE. As the patient was a Jehovah's witness the treating team was unable to use gammaglobulin therapy; they instead relied on combined plasmapheresis and rituximab. To exclude the possibility that the affected members of this family shared a gene coding for an abnormal configuration of the NMDA receptor subunit 1 we sequenced the region of the GRIN1 gene in DNA extracted from blood in both Ms A and her grandmother. Ms A's condition improved dramatically, though her long-term memory is still demonstrably impaired. No genetic abnormality was detected. This case emphasizes how important it is, for a first episode psychosis, to exclude ANRE and other autoimmune synaptic encephalitides, even in the face of significant family history, and if seronegative, the importance of testing for CSF autoantibodies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Mol. Psychiatry 2015 Apr 20: 433-9 |
| PMID | 24912493 |
| Title | Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia. |
| Abstract | Hippocampal dysfunction in schizophrenia is widely acknowledged, yet the mechanism of such dysfunction remains debated. In this study we investigate the excitatory and inhibitory hippocampal neurotransmission using two complementary methodologies, proton magnetic resonance spectroscopy (MRS) and tissue biochemistry, sampling individuals with schizophrenia in vivo and postmortem hippocampal tissue in vitro. The results show significantly lower glutamate concentrations in hippocampus in schizophrenia, an in vivo finding mirrored by lower GluN1 protein levels selectively in the dentate gyrus (DG) in vitro. In a mouse model with a DG knockout of the GRIN1 gene, we further confirmed that a selective decrease in DG GluN1 is sufficient to decrease the glutamate concentrations in the whole hippocampus. Gamma-aminobutyric acid (GABA) concentrations and GAD67 protein were not significantly different in hippocampus in schizophrenia. Similarly, GABA concentrations in the hippocampi of mice with a DG knockout of the GRIN1 gene were not significantly different from wild type. These findings provide strong evidence implicating the excitatory system within hippocampus in the pathophysiology of schizophrenia, particularly indicating the DG as a site of pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | Transl Psychiatry 2016 -1 6: e778 |
| PMID | 27070406 |
| Title | Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801. |
| Abstract | It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene GRIN1 (GRIN1(?PV) mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that GRIN1(?PV) mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, GRIN1(?PV)mice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in GRIN1(?PV)mice, MK-801 induced medial-prefrontal delta (4?Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated GRIN1(?PV)mice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | Neuropharmacology 2016 Jun 105: 61-71 |
| PMID | 26748053 |
| Title | Reversal of social deficits by subchronic oxytocin in two autism mouse models. |
| Abstract | Social deficits are a hallmark feature of autism spectrum disorder (ASD) and related developmental syndromes. Although there is no standard treatment for social dysfunction, clinical studies have identified oxytocin as a potential therapeutic with prosocial efficacy. We have previously reported that peripheral oxytocin treatment can increase sociability and ameliorate repetitive stereotypy in adolescent mice from the C58/J model of ASD-like behavior. In the present study, we determined that prosocial oxytocin effects were not limited to the adolescent period, since C58/J mice, tested in adulthood, demonstrated significant social preference up to 2 weeks following subchronic oxytocin treatment. Oxytocin was also evaluated in adult mice with underexpression of the N-methyl-d-aspartate receptor NR1 subunit (encoded by GRIN1), a genetic model of autism- and schizophrenia-like behavior. Subchronic oxytocin had striking prosocial efficacy in male GRIN1 knockdown mice; in contrast, chronic regimens with clozapine (66 mg/kg/day) or risperidone (2 mg/kg/day) failed to reverse deficits in sociability. Neither the subchronic oxytocin regimen, nor chronic treatment with clozapine or risperidone, reversed impaired prepulse inhibition in the GRIN1 knockdown mice. Overall, these studies demonstrate oxytocin can enhance sociability in mouse models with divergent genotypes and behavioral profiles, adding to the evidence that this neurohormone could have therapeutic prosocial efficacy across a spectrum of developmental disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |