26^th European Neurology Congress

Accumulating evidence suggest that disrupted-in-schizophrenia 1 (DISC1) modulates dopamine mediated function and involved in gene transcription in the brain. Our study was focused on these novel functions of DISC1 in the dopamine system. We demonstrated that DISC1-deficient mice showed an increase in dopamine D1 receptor (DRD1) transcripts in striatal region of the brain. DISC1-deficiency resulted in facilitation of the psychostimulant effect of cocaine in DISC1-deficient mice. The dopamine 1 antagonist, SCH-23390 blocked the psychostimulant effect of cocaine in DISC1-deficient mice. To elucidate molecular mechanism of this phenomenon, we characterized a novel co-repressor complex for DRD1 gene locus composed of DRRF-mSin3A-DISC1. First, we could find a novel interaction between DISC1 and DRRF mainly co-localized in the nucleus. We also identified mSin3A binding with DRRF and DISC1, interestingly the binding intensity between DRRF and mSin3A was signifi cantly increased by DISC1 co-expression. Furthermore, we observed an altered dopamine receptor mediated signaling in cultured striatal neurons (DIV 7) from DISC1-deficient mice. The basal level of cAMP and p-ERK were remarkably increased in DISC1 mutant mice. Taken together, we demonstrate a role of DISC1 in the striatum during cocaine sensitization, suggesting distinct mechanism of DISC1 in modulation of dopamine system through DRRF-mSinA-DISC1 corepressor complex for DRD1 gene.