1. ¹Genes Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
2. ²Department of Psychiatry, Warneford Hospital, University of Oxford, Headington, Oxford, UK

Correspondence: Dr BK Lipska, Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Dr, Rm 4N306, Bethesda, MD 20892-1385, USA. Tel: +1 301 496 9501; Fax: +1 301 402 2751; E-mail: lipskab@intra.nimh.nih.gov

Received 5 November 2007; Revised 17 December 2007; Accepted 17 December 2007; Published online 6 February 2008.

Abstract

Genetic variation in the metabotropic glutamate receptor 3 (GRM3, mGluR3) has been associated with schizophrenia, but the mechanism by which it confers risk is unknown. Previously, we reported the existence of a splice variant, GRM34, which has an exon 4 deletion and encodes a truncated form of the receptor that is expressed in brain. The aim of the present study was to determine whether expression of this splice variant is altered in individuals with schizophrenia and is affected by a risk genotype. We measured GRM3 and GRM34 transcripts in human dorsolateral prefrontal cortex (DLPFC) and hippocampus of the CBDB/NIMH collection (70 controls, 30 schizophrenia patients) and in the DLPFC of the Stanley Array Collection. Expression data of GRM3 mRNA in the DLPFC were inconsistent: GRM3 was increased in schizophrenia patients in the CBDB/NIMH collection, but not in the Stanley Array Collection. GRM3 expression did not change in the frontal cortex of rats treated chronically with haloperidol or clozapine. An exon 3 SNP previously associated with schizophrenia (rs2228595) predicted increased expression of the GRM34 splice variant. Our results suggest that rs2228595, or a neighboring SNP in linkage disequilibrium with it, may contribute to risk for schizophrenia by modulating GRM3 splicing.