Striatal synaptic Abnormalities in Models of Autism

描述(由申请人提供)：自闭症谱系障碍(ASD)是一种常见的、影响社交、交流和重复行为的衰弱障碍。最近的遗传学研究发现，突触细胞黏附基因及其在中央突触编码相互作用蛋白伙伴的基因突变是自闭症谱系障碍的遗传原因。我们创造了一种新的基于神经连接蛋白-1缺失的自闭症小鼠模型。这些小鼠有选择性的、过度重复的行为异常，可能与自闭症有关。我们的初步数据有力地表明，纹状体中NMDA受体功能的下降是这种重复行为表型的一个原因。我们现在建议进行实验，以详细研究该基因缺失对皮质-纹状体突触功能的影响。此外，我们建议使用遗传和药理学方法选择性地挽救/治疗这种表型。因此，我们将能够直接将由于特定分子异常而导致的特定大脑区域中的特定突触与异常行为联系起来，这是神经科学的一个重要基本目标。这些实验将确定强迫症类重复行为的新的突触和电路水平的机制。此外，我们希望为自闭症患者的子集确定针对这些行为的新治疗目标。

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) are common, debilitating disorders affecting social interaction, communication, and repetitive behaviors. Recent genetic findings have identified mutations in synaptic cell adhesion genes and genes encoding their interacting protein partners at central synapses as genetic causes of autism spectrum disorders. We have created a novel autism model mouse line based on deletion of neuroligin-1. These mice have selective, excessive repetitive behavioral abnormalities of potential relevance to autism. Our preliminary data strongly implicate a decrease in NMDA receptor function in the striatum as a cause of this repetitive behavior phenotype. We now propose experiments to examine the effect of deletion of this gene on cortico-striatal synaptic function in detail. Furthermore, we propose to selectively rescue/treat this phenotype using genetic and pharmacologic approaches. Thus, we will be able to directly connect a specific synapse in a specific brain region due to a specific molecular abnormality with an abnormal behavior, an important basic goal in neuroscience. These experiments will identify novel synaptic and circuit-level mechanisms for obsessive-compulsive disorder- like repetitive behaviors in general. In addition, we hope to identify novel treatment targets for these behaviors for a subset of autistic patients.