Elucidating the Effect of Disc 1 on Neurodevelopment and Synaptic Transmission

描述（由申请方提供）：鉴定了导致SCZ易感性的罕见突变，具有相对较高的突变率，从而开发了经证实具有病因学相关性的小鼠模型。DISC1是一个通过罕见的遗传损伤、与SCZ和心境障碍分离的平衡染色体易位在一个大家系中鉴定的易感基因。我们使用了一种以疾病为中心的敲入方法，在小鼠Disc1直向同源物中引入截短损伤，旨在模拟这种易位的影响。在第一轮资助中，我们发现Disc1突变小鼠在空间工作记忆测试中表现出特定和强烈的缺陷。我们还发现了新生儿和成人神经发生过程中齿状回广泛的细胞结构改变，其中包括轴突寻路错误，并伴随着神经活动和短期可塑性的变化。我们还发现cAMP水平的失调有助于结构连接缺陷。最后，我们提供的证据表明，突变小鼠改变了功能连接的前额叶区与颞叶结构。基础上 基于这些发现，本文拟完成Disc1突变对海马的影响分析，并将我们的结构和功能分析扩展到前额叶皮层，最后分析模拟突变对这两个区域之间的通信的影响。除了我们之前从Disc1突变小鼠中获得的结果外，我们提出的研究还受到其他罕见突变模型的平行分析的支配，这提供了比较结果的机会，确定了关键的共同途径，并能够开发出精神分裂症发病机制和病理生理学的全面综合模型。这些知识将有助于发现新的治疗方法和生物标志物。 公共卫生相关性：精神分裂症是一种常见而复杂的精神疾病，具有很强的遗传成分。这个提议本质上是翻译性的，旨在确定精神分裂症易感基因引起的异常大脑结构和功能的特定模式。识别这些模式将有助于旨在逆转潜在病理生理学和恢复正常功能的新疗法。

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. PUBLIC HEALTH RELEVANCE: Schizophrenia is a common and complex psychiatric disorder with a strong genetic component. This proposal is inherently translational in nature, aimed at identifying specific patterns of abnormal brain structure and function caused by schizophrenia predisposing genes. Identifying such patterns would facilitate novel approaches to therapies aimed at reversing the underlying pathophysiology and restoring normal function.