Elucidating the Effect of Disc 1 on Neurodevelopment and Synaptic Transmission

描述（由申请人提供）：对具有相对高外显率的SCZ易感性的罕见突变的鉴定导致了已证实与病因相关的小鼠模型的发展。DISC1是一种易感基因，通过一种罕见的遗传病变，一种与SCZ和情绪障碍分离的平衡染色体易位，在一个大的家系中被发现。我们使用以疾病为中心的敲入方法在小鼠Disc1同源体中引入截断病变，旨在模拟这种易位的影响。在第一轮拨款中，我们发现Disc1突变小鼠在空间工作记忆测试中表现出特异性和强大的缺陷。我们还发现，在新生儿和成人神经发生过程中，齿状回的细胞结构发生了广泛的改变，包括轴突寻路错误，并伴随着神经活动和短期可塑性的变化。我们还发现cAMP水平的失调会导致结构连通性缺陷。最后，我们提供的证据表明，突变小鼠改变了前额叶区域与颞叶结构的功能连接。基础上

DESCRIPTION (provided by applicant): The identification of rare mutations that result in predisposition to SCZ with relatively high penetrance has led to the development of mouse models of proven etiologic relevance. DISC1 is a susceptibility gene identified through a rare genetic lesion, a balanced chromosomal translocation segregating with SCZ and mood disorders in a large pedigree. We used a disease-focused knock-in approach to introduce a truncating lesion in the murine Disc1 orthologue designed to model the effects of this translocation. During the first round of this grant we showed that Disc1 mutant mice display specific and robust deficiencies in spatial working memory tests. We also uncovered widespread cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal pathfinding and are accompanied by changes in neural activity and short-term plasticity. We also showed that dysregulation of cAMP levels contributes to the structural connectivity deficits. Finally we provided evidence that mutant mice have altered functional connectivity of prefrontal areas with temporal lobe structures. Building on these findings, here we propose to complete our analysis on the effect of the Disc1 mutation on hippocampus, extend our structural and functional analysis to prefrontal cortex and finally analyze the effect of the modeled mutation on the communication between these two areas. In addition to our previous results from Disc1 mutant mice our proposed research is dictated by parallel analysis of other models of rare mutations, which affords the opportunity to compare results, identify key common pathways and enable development of a comprehensive and integrative model of schizophrenia pathogenesis and pathophysiology. This knowledge will facilitate discovery of novel treatments and biomarkers.