Behavioral phenotypes of genetic mouse models of autism.
Behavioral phenotypes of genetic mouse models of autism.
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DOI：
10.1111/gbb.12256
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Crawley JN
中科院分区：
文献类型：
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作者：
Kazdoba TM;Leach PT;Crawley JN
100多个从头开始的单基因突变和拷贝数变异与自闭症有关，每个都发生在一小部分病例中。具有同线突变的突变小鼠模型提供了研究工具，以了解每个基因在调节与自闭症相关的生物学和行为表型中的作用。在自闭症谱系障碍和共病神经发育障碍中检测到的风险基因突变的基因敲除、敲除和转基因小鼠现在已经广泛使用。目前，自闭症谱系障碍的诊断完全是根据行为标准。我们开发了一系列小鼠行为分析，旨在最大限度地提高对自闭症诊断关键的社会缺陷和重复行为类型的表面有效性。自闭症相关症状的小鼠行为分析经常包括在表型分析中，这些症状包括认知不灵活、焦虑、多动和对感觉刺激的异常反应。在过去的10年里，我们和世界各地的许多其他实验室利用这些和额外的行为测试来对大量自闭症突变小鼠模型进行表型分析。在这篇综述中，我们重点介绍了基因突变的小鼠模型，这些基因被确定为自闭症的危险基因，这些基因通过突触机制和mTOR信号通路发挥作用。在遗传小鼠模型中，与自闭症相关的健壮、可复制的行为结果证实了自闭症病因学中特定基因贡献和下游生物学机制的因果作用。
More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism.