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, GRM3Δ4, 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 GRM3Δ4 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 GRM3Δ4 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.
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Acknowledgements
LJS is a student in the NIH/Oxford Graduate Partnership Program. This research was supported by the Intramural Research Program of the NIH, NIMH. Post-mortem brain tissue was donated by the Stanley Medical Research Institute, courtesy of Drs Michael B Knable, E Fuller Torrey, Maree J Webster, Serge Weis, and Robert H Yolken. We thank Ms Cara Horowitz, Ms Tricia Peters, and Mr Krishna Vakkalanka for their excellent technical assistance, Dr Mary M Herman for her neuropathological assessments, and Amy Deep-Soboslay for her work on the demographic and clinical data. We thank the staff of the Offices of the Chief Medical Examiner of District of Columbia and of Northern Virginia for their assistance. We also thank the families of the deceased, who generously donated brain tissue as well as their time and effort to make this study possible.
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Dr Harrison's research is supported by the United Kingdom Medical Research Council, Stanley Medical Research Institute, National Alliance for Research on Schizophrenia and Depression, Wellcome Trust, and an unrestricted grant from GlaxoSmithKline. In the past 3 years, Dr Harrison has received honoraria for giving educational lectures or chairing scientific meetings from Bristol-Meyers Squibb, GlaxoSmithKline, Janssen, Lilly, Merck, Sanofi, and Servier pharmaceutical companies, and has been an adviser to Curidium, Janssen, and Wyeth. The other authors declare that, except for income received from the primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
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Sartorius, L., Weinberger, D., Hyde, T. et al. Expression of a GRM3 Splice Variant is Increased in the Dorsolateral Prefrontal Cortex of Individuals Carrying a Schizophrenia Risk SNP. Neuropsychopharmacol 33, 2626–2634 (2008). https://doi.org/10.1038/sj.npp.1301669
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DOI: https://doi.org/10.1038/sj.npp.1301669
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