Multidimensional approaches to molecular basis of schizophrenia

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Schizophrenia is a devastating neuropsychiatric disorder with a multifactorial background. To search for susceptibility genes for schizophrenia, we have been taking four types of approaches, i) candidate gene, ii) PCP-responsive gene, iii) genome-wide and iv) model mouse approaches. We observed associations of GRM7, SLC1A6, SLC6A5, PDE4A, PLAT and C2orf24 with schizophrenia in approaches i, ii and iii. Comprehensive behavioral analyses, in approach iv, of mouse lines with targeted disruption of homologs of either GRIA4 or GRM3 with which we had previously reported associations of schizophrenia, revealed that GluR4^<-/-> mice showed impaired prepulse inhibition (PPI) and increased response to MK-801 in the open field test, and mGluR3^<-/-> mice exhibited hyperactivity in the open field and light/dark transition tests and impaired working memory in the T-maze test, suggesting involvement of these genes in generating schizophrenia endophenotypes.