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、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。我们建议创建新的自闭症模型小鼠系。我们将对这种突触自闭症基因进行条件性敲除和全局彻底敲除，以模仿与自闭症有关的基因完全缺失，这是该基因最常见的突变。到目前为止，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基因敲除构建物的胚系传递，从而为条件基因敲除系和全局基因敲除系建立了创始人。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、生化、电生理学和行为表征。特别是，我们将在这些小鼠系中测量与自闭症谱系障碍的三个核心症状领域中的每一个相对应的行为。其结果将是一种新的自闭症小鼠遗传模型，该模型与自闭症的行为相关性，并利用电生理学对大脑功能进行初步研究，以了解对皮质突触的影响。 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，并使用此类原因的动物模型来确定治疗方法。这份为期两年的R21提案充分利用了我们在创建一种新的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迅速推进这一项目。我们对大脑病理的理解与这些小鼠的行为异常相结合，将导致在模型中以及最终在自闭症患者中对自闭症症状进行药物治疗的可测试假说。

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.