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

描述（由申请人提供）：精确的突触连接对神经系统的正常功能至关重要，许多神经系统疾病都涉及突触连接缺陷。然而，体内调节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中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）最初被鉴定为与PSD95家族和Shank家族蛋白相互作用的蛋白，后者是兴奋性突触中另外两个主要的多结构域支架蛋白。这三组蛋白共同构成了一个关键的支架复合物，以锚定/靶向神经递质受体和信号分子到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。它们在突触后密度中高度富集，并且只在兴奋性突触中表达，这与它们在突触后支架中的作用一致。在这项资助申请中，我们建议结合遗传，生化，电生理和行为方法来确定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中高表达的成员，纹状体是强迫症谱系障碍发病的主要脑区。我们发现，小鼠SAPAPS基因的基因缺失会导致强迫性梳理行为，导致面部毛发去除和皮肤损伤，并伴有显著增加的焦虑。此外，生化和电生理研究都揭示了突变小鼠的皮质纹状体突触缺陷。这些数据有力地表明SAPAPS在皮质纹状体突触中起着重要作用，从而为我们提供了一个独特的机会来解剖导致小鼠强迫症样行为发展的突触机制。强迫症是第二常见的神经精神疾病，约占人口的2%。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可能导致强迫症的发病机制。

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.