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。我们建议创建新的自闭症模型小鼠系。我们将产生一个有条件的敲除和一个全局的，完全的敲除突触自闭症基因来模拟完全的基因缺失，这是与自闭症相关的最常见的基因突变。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敲除结构的种系传播，从而建立了条件和全局敲除系的创始人。我们现在建议扩大这些新的自闭症模型小鼠系，并进行初步的分子，生化，电生理和行为表征。特别是，我们将在这些小鼠系中测量自闭症谱系障碍的三个核心症状域对应的行为。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，以及使用电生理学来了解皮质突触影响的脑功能的初步研究。

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.