Roles of SAPAP Proteins in Synaptic Function and Compulsive-like Behavior

描述(由申请人提供)：精确的突触连接对于神经系统的正常功能是必不可少的，缺陷与许多神经疾病有关。然而，调节体内突触组装和功能的机制仍然知之甚少。作为了解兴奋性突触关键支架蛋白在体内功能的第一步，我们启动了SAP90/PSD95相关蛋白(SAPAPs)的分子遗传学研究。SAPAP家族蛋白(SAPAP1-4)最初被确定为与PSD95家族和Shank家族蛋白相互作用的蛋白质，这两种蛋白是兴奋性突触中另外两个主要的多结构域支架蛋白。这三组蛋白质一起被提出形成一个关键的支架复合体，将神经递质受体和信号分子锚定/靶向兴奋性突触的突触后膜。我们发现SAPAP家族蛋白在大脑中广泛表达，但存在差异表达。它们高度富含突触后密度，并且仅在兴奋性突触表达，这与它们在突触后支架中的作用一致。在这项拨款申请中，我们建议结合遗传学、生化、电生理学和行为学的方法来确定SAPAPS在突触发育和功能中的作用，以及它在强迫症(OCD)样行为中的意义。SAPAPS是SAPAP基因家族中唯一在纹状体高表达的成员，纹状体是参与强迫症谱系障碍发病的主要大脑区域。我们发现，小鼠SAPAPS基因的基因缺失会导致强迫的梳妆行为，导致面部脱毛和皮肤损伤，并伴随着显著增加的焦虑。此外，生化和电生理研究都显示，突变小鼠的皮质-纹状体突触存在缺陷。这些数据有力地表明SAPAPS在皮质-纹状体突触中发挥着重要作用，从而为我们提供了一个独特的机会来剖析导致小鼠强迫症样行为发展的突触机制。强迫症是第二种最常见的神经精神疾病，影响到约2%的人口。这项研究将利用小鼠遗传学的力量来确定神经元连接缺陷如何参与强迫症的发病机制。

DESCRIPTION (provided by applicant): Precise synaptic connectivity is essential for the proper function of the nervous system and defects are implicated in many neurological disorders. However, the mechanisms regulating the assembly and function of synapses in vivo are still poorly understood. As a first step toward understanding the in vivo function of key scaffolding proteins at excitatory synapses we initiated a molecular genetic study on SAP90/PSD95 associated proteins (SAPAPs). SAPAP family proteins (SAPAP1-4) were originally identified as proteins interacting with PSD95 family and Shank family proteins, two other major multidomain scaffolding proteins at excitatory synapses. Together these three groups of proteins have been proposed to form a key scaffolding complex to anchor/target neurotransmitter receptors and signaling molecules to the postsynaptic membrane of excitatory synapses. We found that SAPAP family proteins are widely, yet differentially expressed in the brain. They are highly enriched in the postsynaptic density, and exclusively expressed at excitatory synapses, consistent with their proposed role in postsynaptic scaffolding. In this grant application we propose to combine genetic, biochemical, electrophysiological and behavioral approaches to determine the role of SAPAPS in synaptic development and function, and its implication in obsessive compulsive disorder (OCD)-like behavior. SAPAPS is the only member of the SAPAP gene family that is highly expressed in the striatum, a major brain region involved in pathogenesis of OCD spectrum disorders. We found that genetic deletion of SAPAPS gene in mice results in compulsive grooming behavior leading to facial hair removal and skin lesions, accompanied by significantly increased anxiety. Furthermore, both biochemical and electrophysiological studies reveal cortico-striatal synaptic defects in the mutant mice. These data strongly suggest that SAPAPS plays an important role at cortico-striatal synapses, and thus provide us a unique opportunity to dissect the synaptic mechanisms leading to the development of OCD-like behavior in mice. Obsessive-compulsive disorder is the second most prevalent neuropsychiatric disease, affecting ~2% of the population. This study will use the power of mouse genetics to determine how defects in neuronal connectivity may contribute to the pathogenesis of obsessive-compulsive disorder.