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，影响社会互动，沟通和重复行为的衰弱性障碍。最近的遗传学研究发现，突触细胞粘附基因和编码它们在中央突触的相互作用蛋白伴侣的基因的突变是自闭症谱系障碍的遗传原因。我们基于神经胶质素-1的缺失建立了一种新的自闭症模型小鼠系。这些老鼠有选择性的、过度重复的行为异常，可能与自闭症有关。我们的初步数据强烈暗示，纹状体中NMDA受体功能的减少是导致这种重复行为表型的原因。我们现在建议进行实验来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，我们将能够将由于特定分子异常而导致的大脑特定区域的特定突触与异常行为直接联系起来，这是神经科学的一个重要基础目标。这些实验将确定新的突触和电路水平机制强迫症-像一般的重复行为。此外，我们希望为一部分自闭症患者的这些行为确定新的治疗目标。

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.