Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growing evidence suggests that NMDA receptor (NMDAR) dysfunction may be involved in schizophrenia. The NMDAR is a multimeric assembly derived from seven different genes (NR1, NR2A-2D and NR3A-3B). While region-specific changes in the expression of most NMDAR subunits have been reported in schizophrenia, possible abnormalities of NR3A expression have not been investigated. Both electrophysiological and anatomical data in rodents, however, suggest that NR3A subunits could play a role in this disorder. In this study, we measured NR3A transcript levels in the dorsolateral prefrontal cortex (DLPFC) and inferior temporal neocortex in the brains of people with schizophrenia, bipolar disorder, depression, and a comparison group. This transcript was elevated by 32% in schizophrenia relative to controls, but only in the DLPFC and not inferior temporal cortical regions. Interestingly, this effect was restricted to gyral aspects of the DLPFC and did not involve sulcal areas. NR3A mRNA was significantly decreased by 12% in bipolar disorder relative to the comparison group in DLPFC, although there were no gyral versus sulcal differences. As was the case in schizophrenia, no changes in NR3A expression were observed in the inferior temporal cortex in bipolar disorder. These data indicate that the NR3A subunit is abnormally expressed in both schizophrenia and bipolar disorder.
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PMID:NR3A NMDA receptor subunit mRNA expression in schizophrenia, depression and bipolar disorder. 1547 7

Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memory-related signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer's and Parkinson' disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies.
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PMID:NMDA receptors are not alone: dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling. 1671 8

Subunit composition of N-methyl-D-aspartate-type glutamate receptors (NMDARs) dictates their function, yet the ontogenic profiles of human NMDAR subunits from gestation to adulthood have not been determined. We examined NMDAR mRNA and protein development in human dorsolateral prefrontal cortex (DLPFC), an area in which NMDARs are critical for higher cognitive processing and NMDAR hypofunction is hypothesized in schizophrenia. Using quantitative reverse transcriptase-polymerase chain reaction and western blotting, we found NR1 expression begins low prenatally, peaks in adolescence, yet remains high throughout life, suggesting lifelong importance of NMDAR function. In contrast, NR3A levels are low during gestation, surge soon after birth, and decline progressively through adolescence and into adulthood. Because NR3A subunits uniquely attenuate NMDAR-mediated currents, limit calcium influx, and suppress dendritic spine formation, high levels during early childhood may be important for regulating neuroprotection and activity-dependent sculpting of synapses. We also examined whether subunit changes underlie reduced NMDAR activity in schizophrenia. Our results reveal normal NR1 and NR3A protein levels in DLPFC from schizophrenic patients, indicating that NMDAR hypofunction is unlikely to be maintained by gross changes in NR3A-containing NMDARs or overall NMDAR numbers. These data provide insights into NMDAR functions in the developing CNS and will contribute to designing pharmacotherapies for neurological disorders.
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PMID:Developmental regulation of the NMDA receptor subunits, NR3A and NR1, in human prefrontal cortex. 1829 32

A hypofunction of the N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Compelling evidence of altered NMDA receptor subunit expression in the schizophrenic brain has not, however, so far emerged. Rats reared in isolation exhibit several characteristics, including disturbed sensory gating, which resemble those seen in schizophrenia. To explore the possibility that NMDA receptor dysfunction may contribute to the behavioral and neurochemical consequences of rearing rats in isolation, we compared NMDA receptor subunit expression in brains of rats which were housed in isolation and which displayed a deficit in prepulse inhibition of the acoustic startle response with that of socially housed controls. An initial microarray analysis revealed a 1.26-fold increase in NR2A transcript in the prefrontal cortex, but not in the nucleus accumbens, of rats reared in isolation compared with those housed socially. In contrast, NR1, NR2B, NR2C, NR2D, NR3A, and NR3B subunit expression was unchanged in either brain area. In a second cohort of animals, in situ hybridization revealed increased NR2A mRNA expression in the medial prefrontal cortex, an observation that was substantiated by increased [(3)H]CGP39653 binding suggesting that NR2A receptor subunit protein expression was also elevated in the medial prefrontal cortex of the same animals. No changes in expression of NR1 or NR2B subunits were observed at both mRNA and protein level. Altered NR2A subunit expression in the medial prefrontal cortex of rats reared in isolation suggests that NMDA receptor dysfunction may contribute to the underlying pathophysiology of this preclinical model of aspects of schizophrenia.
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PMID:Increased expression of the NR2A NMDA receptor subunit in the prefrontal cortex of rats reared in isolation. 1953 26

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.
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PMID:Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. 2283 10

Disturbances in glutamate signaling caused by disruption of N-methyl-D-aspartate-type glutamate receptor (NMDAR) have been implicated in schizophrenia. Findings suggested that miR-219, miR-132 and miR-107 could involve in NMDAR signaling by influencing the expression of pathway genes or the signaling transmission and single nucleotide polymorphisms (SNPs) within miRNA genes or miRNA target sites could result in their functional changes. Therefore, we hypothesized that SNPs in miRNAs and/or their target sites were associated with schizophrenia. 3 SNPs in hsa-pri-miR-219/132/107 and 6 SNPs in 3'UTRs of GRIN2A/2B/3A and CAMK2G were selected and genotyped in a case-control study of 1041 schizophrenia cases and 953 healthy controls in Chinese Han population. In the present study, GRIN2B rs890 showed significant associations with schizophrenia. Further functional analyses showed that the rs890 variant C allele led to significantly lower luciferase activity, compared with the A allele. MDR analysis showed that a 4-locus model including rs107822, rs2306327, rs890 and rs12342026 was the best model. These findings suggest that GRIN2B may be associated with schizophrenia and interaction effects of the polymorphisms in hsa-miR-219, CAKM2G, GRIN2B and GRIN3A may confer susceptibility to schizophrenia in the Chinese Han population.
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PMID:Polymorphisms in MicroRNA Genes And Genes Involving in NMDAR Signaling and Schizophrenia: A Case-Control Study in Chinese Han Population. 2625 37

The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation.
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PMID:Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study. 2659 62

In schizophrenia (SCZ) and autism spectrum disorder (ASD), the dysregulation of glutamate transmission through N-methyl-D-aspartate receptors (NMDARs) has been implicated as a potential etiological mechanism. Previous studies have accumulated evidence supporting NMDAR-encoding genes' role in etiology of SCZ and ASD. We performed a screening study for exonic regions of GRIN1, GRIN2A, GRIN2C, GRIN2D, GRIN3A, and GRIN3B, which encode NMDAR subunits, in 562 participates (370 SCZ and 192 ASD). Forty rare variants were identified including 38 missense, 1 frameshift mutation in GRIN2C and 1 splice site mutation in GRIN2D. We conducted in silico analysis for all variants and detected seven missense variants with deleterious prediction. De novo analysis was conducted if pedigree samples were available. The splice site mutation in GRIN2D is predicted to result in intron retention by minigene assay. Furthermore, the frameshift mutation in GRIN2C and splice site mutation in GRIN2D were genotyped in an independent sample set comprising 1877 SCZ cases, 382 ASD cases, and 2040 controls. Both of them were revealed to be singleton. Our study gives evidence in support of the view that ultra-rare variants with loss of function (frameshift, nonsense or splice site) in NMDARs genes may contribute to possible risk of SCZ.
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PMID:Rare loss of function mutations in N-methyl-D-aspartate glutamate receptors and their contributions to schizophrenia susceptibility. 2931 96

The N-methyl-d-aspartate receptor (NMDAR) has been implicated in the pathophysiology of neurological diseases, such as schizophrenia, autism spectrum disorders (ASD), and Alzheimer's disease (AD), whose unique clinical hallmark is a constellation of impaired social and/or cognitive behaviors. GluN3A (NR3A) is a unique inhibitory subunit in the NMDAR complex. The role of GluN3A in social behavioral activities is obscure. In this study, we sought to evaluate altered social activities in adult GluN3A knockout (KO) mice. GluN3A KO mice spent less time in reciprocal social interaction in the social interaction test compared to wild-type (WT) mice. A social approach test using a three-chamber system confirmed that mice lacking GluN3A had lower sociability and did not exhibit a preference for social novelty. GluN3A KO mice displayed abnormal food preference in the social transmission of food preference task and low social interaction activity in the five-trial social memory test, but without social memory deficits. Using a home cage monitoring system, we observed reduced social grooming behavior in GluN3A KO mice. Signaling genes that might mediate the altered social behaviors were examined in the prefrontal cortex, hippocampus, and thalamus. Among nine genes examined, the expression of the oxytocin receptor was significantly lower in the prefrontal cortex of GluN3A KO mice than that in WT mice. Oxytocin treatment rescued social activity deficits in GluN3A KO mice. These findings support a novel idea that a chronic state of moderate increases in NMDAR activities may lead to downregulation of the oxytocin signaling and impaired behavioral activities that are seen in psychiatric/neurodegenerative disorders.
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PMID:Impaired social behaviors and minimized oxytocin signaling of the adult mice deficient in the N-methyl-d-aspartate receptor GluN3A subunit. 2955 74

The objective of this study was to compare the expression of genes involved in the reelin pathway, in the post-mortem brain of individuals with schizophrenia (SZ) and mood disorders (MD) with a healthy control (HC) group; and to investigate the role f body mass index (BMI) as a potential mediator. The "Gene Expression in Postmortem dlPFC and Hippocampus from Schizophrenia and Mood Disorders" study holds microarray data on individuals with SZ, MD and HCs (from whom 849 specimens are from the dlPFC and 579 from the hippocampus). mRNA data was obtained using HumanHT-12 v4 BeadChip arrays (Illumina). Multivariate analysis of covariance were used to investigate the main effects of group and relevant covariates on RELNm, NOTCH1, GRIN1m, GRIN3A, CAMK2Gm, CAMK2A, CAMK2Bm, CAMK2N2, GRIN2Bm, GRIN2A, CREBBPm, APOE, LDLR and DAB1 gene expression. In the dlPFC, individuals with SZ had higher expression, relative to HCs, of APOE. Individuals with MD had higher expression, relative to HCs, of CAMK2A, CAMK2N2, and GRIN2Bm. Moreover, individuals with MD had higher expression, relative to SZ patients, of CAMK2N2. There were significant group by BMI effects for expression of RELN, CAMK2A, CAMK2N2, and GRIN2A. In the hippocampus, individuals with MD had lower expression, relative to HCs, of APOE. The results of this study suggest that the expression of genes related to the reelin pathway could be different between individuals with SZ and MD and healthy controls, with a greater vulnerability associated with greater BMI.
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PMID:The impact of body mass index in gene expression of reelin pathway mediators in individuals with schizophrenia and mood disorders: A post-mortem study. 2968 May 75


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