Shank3 in Synaptic Function and Autism

描述(申请人提供)：最近的遗传学和基因组研究发现了大量自闭症谱系障碍(ASD)的候选基因，其中许多编码突触蛋白，表明突触功能障碍可能在自闭症谱系障碍中起关键作用。最有希望的ASD候选基因之一是Shank3。Shank家族蛋白(Shank1-3)直接与SAPAP结合形成PSD95/SAPAP/Shank复合体。这种蛋白质的核心被认为是一个支架，协调大分子突触后信号复合体的组装。它们被认为在突触后离子型谷氨酸受体的运输和锚定以及谷氨酸能突触的发育中发挥重要作用。SHANK3是Shank家族中唯一在纹状体高表达的成员，纹状体是与自闭症密切相关的大脑区域。为了研究Shank3在突触中的体内功能，并阐明Shank3的破坏如何导致自闭症，我们培育了Shank3突变小鼠。我们发现，Shank3基因的破坏导致了皮质-纹状体突触的结构和功能的变化。此外，Shank3突变小鼠表现出强迫/重复行为和社交互动受损，这与自闭症的两个基本特征相似。总之，我们的研究证明了Shank3在体内皮质-纹状体突触结构和功能中的关键作用，并建立了Shank3基因的破坏与小鼠自闭症样行为发生之间的因果关系。因此，Shank3突变小鼠为我们提供了一个很好的机会来剖析与人类ASD相关的异常行为背后的神经回路机制。我们建议结合遗传学、光遗传学、电生理学和行为学的方法来实现以下目标：(1)研究Shank3突变小鼠的纹状体内微回路功能障碍。(2)确定基底节直接通路和间接通路在重复行为中的相对作用。(3)解剖Shank3突变小鼠社会交往缺陷所涉及的神经回路。总之，这些研究可能会显著增强我们对自闭症样行为的神经回路机制的理解，并可能有助于开发更有效的治疗新策略。

DESCRIPTION (provided by applicant): Recent genetic and genomic studies have identified a large number of candidate genes for autism spectrum disorders (ASDs), many of which encode synaptic proteins, suggesting synaptic dysfunction may play a critical role in ASDs. One of the most promising ASD candidate genes is Shank3. Shank family proteins (Shank1-3) directly bind SAPAP to form the PSD95/SAPAP/Shank complex. This core of proteins is thought to function as a scaffold, orchestrating the assembly of the macromolecular postsynaptic signaling complex. They have been proposed to play important roles in trafficking and anchoring of postsynaptic ionotropic glutamate receptors and the development of glutamatergic synapses. Shank3 is the only member of the Shank family highly expressed in the striatum, a brain region strongly implicated in ASDs. To investigate the in vivo function of Shank3 at synapses and to elucidate how a disruption of Shank3 may lead to ASDs, we generated Shank3 mutant mice. We found that disruption of Shank3 resulted in both structural and functional changes in cortico-striatal synapses. Furthermore, Shank3 mutant mice exhibit compulsive/repetitive behavior and impaired social interaction, which resemble two of the cardinal features of ASDs. Together, our studies demonstrate a critical role for Shank3 in cortico-striatal synaptic structure and function n vivo and establish causality between a disruption in the Shank3 gene and the genesis of autistic like-behaviors in mice. Thus, the Shank3 mutant mice provide us with an excellent opportunity to dissect the neural circuitry mechanisms underlying the abnormal behaviors relevant to human ASD. We propose to combine genetic, optogenetic, electrophysiological and behavioral approaches to achieve the following goals: (1) To investigate the intrastriatal microcircuitry dysfunction in Shank3 mutant mice. (2) To determine the relative contributions of the direct and indirect pathway of the basal ganglia in repetitive behavior. (3) To dissect neural circuits involved in social interaction deficits in Shank3 mutant mice. Together, these studies may significantly enhance our understanding of neural circuitry mechanisms of autistic-like behaviors and may help to develop novel strategies for more effective treatment.