Multidimensional approaches to molecular basis of schizophrenia

精神分裂症是一种具有多因素背景的毁灭性神经精神障碍。为了寻找精神分裂症的易感基因，我们已经采取了四种方法，i)候选基因，ii) pcp反应基因，iii)全基因组和iv)模型小鼠方法。我们观察了GRM7、SLC1A6、SLC6A5、PDE4A、PLAT和C2orf24在途径i、ii和iii中与精神分裂症的关联。在方法iv中，对我们之前报道的与精神分裂症相关的GRIA4或GRM3的同质物进行了全面的行为分析，结果显示，GluR4^<-/->小鼠在开放领域测试中表现出脉冲前抑制（PPI）受损，对MK-801的反应增加，而mGluR3^<-/->小鼠在开放领域和明暗转换测试中表现出过度活跃，在t -迷宫测试中表现出工作记忆受损。提示这些基因参与了精神分裂症内表型的产生。

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.