A polymorphism of the metabotropic glutamate receptor mGluR7 (GRM7) gene is associated with schizophrenia

Abstract

Introduction: Glutamate dysfunction has been implicated in the pathophysiology of schizophrenia. The metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors. GRM7, the gene that encodes mGluR7, is expressed in many regions of the human central nervous system. The GRM7 gene is located on human chromosome 3p26, which has been suggested by linkage analysis to contain a susceptibility locus for schizophrenia. Methods:We screened for mutations in all exons, exon/intron junctions, and promoter regions of the GRM7 gene in Japanese patients with schizophrenia and evaluated associations between the detected polymorphisms and schizophrenia. We examined the influence of one polymorphism associated with schizophrenia on the expression of GRM7 by dual luciferase assay in transfected cells.Results: Twenty-five polymorphisms/mutations were detected in GRM7. Case-control analysis revealed a potential association of a synonymous polymorphism (371T/C, rs3749380) in exon 1 with schizophrenia in our case-control study of 2293 Japanese patients with schizophrenia and 2382 Japanese control subjects (allelic p = 0.009). Dual luciferase assay revealed suppression of transcription activity by exon 1 containing this polymorphism and a statistically significant difference in the promoter activity between the T and C alleles. Conclusions:Our results support the possible association of a GRM7 gene polymorphism with genetic susceptibility to schizophrenia. 3 IntroductionSchizophrenia is a severe psychiatric disorder, which is equally prevalent in men and women and affects approximately one percent of the population worldwide. Several neurotransmitter systems and functional networks within the brain have been found to be affected in patients with schizophrenia. The glutamatergic neuronal dysfunction hypothesis is one of the main explanatory hypotheses (Carlsson et al., 1997). Glutamate is the primary excitatory neurotransmitter in brain. It is contained as a neurotransmitter in approximately 60% of brain neurons, including almost all cortical pyramidal neurons. Further, virtually 100% of brain neurons contain some type of glutamate receptor. Glutamate mediates its effects on the central nervous system via both ionotropic and metabotropic receptors. The metabotropic glutamate receptors (mGluRs), which are G protein-coupled receptors, are divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties (Nakanishi 1994;Pin and Duvoisin 1995). The mGluRs in group I are mGluR1 and mGluR5, those in group II are mGluR2 and mGluR3, and those in group III are mGluRs 4, 6, 7, and 8. Group II and group III mGluRs are linked to inhibition of the cyclic AMP cascade but differ in their agonist selectivities. mGluR7 is the most highly conserved mGluR subtype across mammalian species (Flor et al., 1997). Makoff et al (1996) observed by in situ hybridization that GRM7 is expressed in many areas of the human brain, especially the cerebral cortex, hippocampus, and cerebellu...

Evidence for schizophrenia susceptibility alleles in the Indian population: An association of neurodevelopmental genes in case–control and familial samples

“…Studied variant (rs17603876) is in LD with rs12155594, associated with transition to psychosis (Bousman et al, 2013). GRM7 variant, rs3864075, has been associated with cognitive phenotype in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study (Need et al, 2009), and its other variants were reported to be associated with schizophrenia (Ohtsuki et al, 2008;Ganda et al, 2009;Shibata et al, 2009). GRM7, a metabotropic glutamate receptor is implicated in glutamate signaling.…”

ADX71743, a Potent and Selective Negative Allosteric Modulator of Metabotropic Glutamate Receptor 7: In Vitro and In Vivo Characterization

“…The amphetamine-induced hyperactivity, DOI-induced head twitch, and CAR tests in rodents have been shown to be sensitive to typical and atypical antipsychotic drugs (Ellenbroek, 1993;Wettstein et al, 1999;Wadenberg, 2010). The rationale for testing ADX71743 in models of psychosis, in part, came from several independent studies showing a link between polymorphisms in mGlu 7 and schizophrenia (Ohtsuki et al, 2008;Ganda et al, 2009;Shibata et al, 2009). ADX71743 resulted in a dose-dependent, albeit modest, reduction of amphetamine-induced hyperactivity in mice.…”

Viral-Mediated Knockdown of mGluR7 in the Nucleus Accumbens Mediates Excessive Alcohol Drinking and Increased Ethanol-Elicited Conditioned Place Preference in Rats

“…As such, dysregulation of mGluR7 has been linked to many psychiatric diseases including depression (Bradley et al, 2011;Cryan et al, 2003), anxiety (Fendt et al, 2008;Mitsukawa et al, 2006), schizophrenia (Bolonna et al, 2001;Ohtsuki et al, 2008) and drug addiction Li et al, 2009Li et al, , 2010. In rodents, results have indicated that the mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082) dose dependently inhibits cocaine-induced enhancement of electrical brainstimulation reward and intravenous cocaine self-administration in rats ).…”