Dachtler James, Elliott Christina, Rodgers R John, Baillie George S, Clapcote Steven J
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK.
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
Sci Rep. 2016 Jan 5;6:18748. doi: 10.1038/srep18748.
Disrupted-in-Schizophrenia 1 (DISC1) is a risk factor for schizophrenia and affective disorders. The full-length DISC1 protein consists of an N-terminal 'head' domain and a C-terminal tail domain that contains several predicted coiled-coils, structural motifs involved in protein-protein interactions. To probe the in vivo effects of missense mutation of DISC1's C-terminal tail, we tested mice carrying mutation D453G within a predicted α-helical coiled-coil region. We report that, relative to wild-type littermates, female DISC1(D453G) mice exhibited novelty-induced hyperlocomotion, an anxiogenic profile in the elevated plus-maze and open field tests, and reduced social exploration of unfamiliar mice. Male DISC1(D453G) mice displayed a deficit in passive avoidance, while neither males nor females exhibited any impairment in startle reactivity or prepulse inhibition. Whole brain homogenates showed normal levels of DISC1 protein, but decreased binding of DISC1 to GSK3β, decreased phospho-inhibition of GSK3β at serine 9, and decreased levels of β-catenin in DISC1(D453G) mice of either sex. Interrupted GSK3β signaling may thus be part of the mechanism underlying the behavioral phenotype associated with D453G, in common with the previously described N-terminal domain mutations Q31L and L100P in mice, and the schizophrenia risk-conferring variant R264Q in humans.
精神分裂症断裂基因1（DISC1）是精神分裂症和情感障碍的一个风险因素。全长DISC1蛋白由一个N端“头部”结构域和一个C端尾部结构域组成，C端尾部结构域包含几个预测的卷曲螺旋结构，这是参与蛋白质-蛋白质相互作用的结构基序。为了探究DISC1 C端尾部错义突变的体内效应，我们测试了在一个预测的α螺旋卷曲螺旋区域携带D453G突变的小鼠。我们报告，相对于野生型同窝小鼠，雌性DISC1（D453G）小鼠表现出新奇诱导的运动亢进，在高架十字迷宫和旷场试验中呈现焦虑样表现型，以及对陌生小鼠的社交探索减少。雄性DISC1（D453G）小鼠在被动回避方面存在缺陷，而雄性和雌性小鼠在惊吓反应或前脉冲抑制方面均未表现出任何损伤。全脑匀浆显示DISC1蛋白水平正常，但DISC1与GSK3β的结合减少，GSK3β在丝氨酸9处的磷酸化抑制作用降低，并且在两性的DISC1（D453G）小鼠中β-连环蛋白水平降低。因此，与小鼠中先前描述的N端结构域突变Q31L和L100P以及人类中赋予精神分裂症风险的变体R264Q一样，GSK3β信号通路中断可能是与D453G相关的行为表型潜在机制的一部分。
