DISC1 genetically interacts with a mental retardation gene in glutamatergic synaptogenesis in Drosophila

Kazuki Kurita, Daisuke Tanaka, Yuko Arai, Katsuo Furukubo-Tokunaga

Graduate School of Life and Environmental Sciences, University of Tsukuba, Japan


Schizophrenia is a debilitating psychiatric disorder that affects about 1% population. Recent human genetic studies in patients with schizophrenia strongly suggest the presence of genetic risk factors underlying the pathogenesis. However, pathophysiological mechanism of schizophrenia remains largely unknown. To further understand the molecular mechanisms underlying pathophysiology of schizophrenia, genetically tractable model animals are challenging but necessary. Disrupted-in-Schizophrenia-1 (DISC1), originally identified at the breakpoint of a chromosome (1;11)(q42.1; q14.3) translocation in large Scottish family, is a susceptibility gene for not only schizophrenia but also other mental disorders including bipolar disorder and mental retardation. We have been interested in developing a Drosophila model in which human DISC1 is overexpressed in the developing nervous system. In order to clarify the complex molecular mechanism of DISC1 in the pathology of schizophrenia and other mental disorders, we adopted to overexpress DISC1 in developing glutamatergic synapses in the fly neuromuscular junctions. We found that DISC1 suppresses the formation of synaptogenesis. Systematic deletion construct assays of DISC1 revealed a critical domain that is importance for the cytoplasmic functions of DISC1 in synaptogenesis. Based on this assay, we have screened other schizophrenia risk factor genes for genetic interactions with DISC1 in synaptogenesis, and found candidate genes that are critical for mental retardation in human. Our findings support the synaptic hypothesis of schizophrenia and mental retardation and suggest common underlying molecular mechanisms for the important mental disorders.