Novel Genetic Animal 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，使人衰弱的疾病，影响社会互动，沟通和重复行为。最近的遗传学研究发现，在突触细胞粘附基因和基因编码的相互作用的蛋白质伴侣在中央突触自闭症谱系障碍的遗传原因的突变。我们建议创建新的自闭症模型小鼠品系。我们将同时产生条件性敲除和全局性的完全敲除这个突触自闭症基因来模拟完全基因缺失，这是与自闭症相关的基因中最常见的突变。迄今为止，我们的进展是实质性的，因为我们现在已经证明了我们的条件性敲除构建体的种系传递，从而建立了条件性和全局敲除系的创始人。我们现在建议扩展这些新的自闭症模型小鼠系，并进行初步的分子，生物化学，电生理和行为表征。特别是，我们将在这些小鼠品系中测量与自闭症谱系障碍的三个核心症状域中的每一个相对应的行为。其结果将是一种新的自闭症遗传模型小鼠系，该模型与自闭症的行为相关性，以及使用电生理学对大脑功能进行的初步研究，以了解对皮层突触的影响。 公共卫生相关性：我们的目标是更好地了解人类自闭症的遗传原因，并使用这种原因的动物模型来确定治疗方法。这项为期2年的R21提案充分利用了我们在创建新型自闭症动物模型方面取得的重大进展，并将使我们能够在短时间内快速推进该项目。我们对大脑病理学的理解与这些小鼠的行为异常的结合将导致关于在模型中并最终在自闭症患者中对自闭症症状进行药物治疗的可验证的假设。

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 propose to create novel autism model mouse lines. We will produce both a conditional knockout as well as a global, complete knockout of this synaptic autism gene to mimic complete gene deletion, the most common mutation of this gene linked to autism. Our progress to date is substantial in that we have now demonstrated germline transmission of our conditional knockout construct, thereby establishing founders for both conditional and global knockout lines. We now propose to expand these novel autism model mouse lines and perform initial molecular, biochemical, electrophysiologic and behavioral characterization. In particular, we will measure behaviors corresponding to each of the three core symptom domains in autism spectrum disorder in these mouse lines. The result will be a novel genetic model mouse line of autism, behavioral relevance of the model to autism, and initial studies on brain function using electrophysiology to understand effects on cortical synapses. PUBLIC HEALTH RELEVANCE: Our goal is to better understand a genetic cause of human autism and to use animal models of such causes to identify treatments. This 2-year R21 proposal capitalizes on our significant progress toward creating a novel animal model of autism and will allow us to rapidly advance this project in a brief period. The marriage of our understanding of brain pathology with behavioral abnormalities in these mice will lead to testable hypotheses regarding pharmacologic treatment of autism symptoms in the model and ultimately in autistic patients.