Cntnap2 in a behavioral model of autism

描述（由申请人提供）：幼儿在语言、社会互动和行为灵活性方面的缺陷共同构成了自闭症谱系障碍（ASD）的特征。语言和自闭症是一种独特的人类表型，但对其神经生理和分子基础的研究需要动物模型。这项提议的长期目标是利用斑胸草雀鸣鸟开发一种新的ASD模型。虽然没有一个单一的模型可以捕捉到自闭症谱系障碍的所有特征，但鸣禽是为数不多的可以研究由习得的声音交流组成的语言子成分的动物之一。这是因为鸣禽与人类一样，与传统的实验室动物不同，它们通过与同种动物的社会互动来学习发声。这一观点的支持来自于比较自闭症易感基因，接触相关蛋白样2 （Cntnap2）在发音学习者和非学习者大脑中的表达模式。在人类和雀类中，Cntnap2在功能上指定为习得性声音交流的区域丰富。相比之下，转录本在啮齿动物大脑中的分布没有显示出区域特异性富集。由于携带CNTNAP2突变的人类表现出ASD和SLI的特征，我们将首先在斑胸草雀端脑神经元培养物中开发降低CNTNAP2水平的小发夹RNA构建物，然后在发育中的胚胎卵中开发。我们将确定Cntnap2减少对体外和体内电生理和神经解剖学特性的影响，以及对声乐学习、其他社交和重复行为的影响。这项工作不仅阐明了Cntnap2在ASD中的作用，还将为利用鸣禽来理解其他自闭症易感基因在社会学习声乐交流中的作用提供一个证明原则。ASD的鸣禽模型有望提供有关细胞和电路效应的关键信息，并将有助于筛选治疗干预措施。我们的研究旨在提供新的方法来改善自闭症儿童的社会互动，从而提高他们的生活质量。

DESCRIPTION (provided by applicant): Impairments in language, social interaction and behavioral flexibility that together occur in young children comprise the hallmarks of autism spectrum disorder (ASD). Language, and thus autism, is a uniquely human phenotype, but studies of its neurophysiological and molecular basis require animal models. The broad long-term objective of this proposal is to develop a novel model of ASD using the zebra finch songbird. While no single model will capture all features of ASD, songbirds are one of the few in which the language subcomponent comprised by learned vocal communication can be studied. This is because songbirds, like humans and unlike traditional laboratory animals, learn their vocalizations through social interactions with conspecifics. Support for this idea comes from comparing the expression patterns of the autism susceptibility gene, contactin-associated protein-like 2 (Cntnap2) in the brains of vocal learners and non-learners. In both humans and finches, Cntnap2 is enriched in regions that are functionally specified for learned vocal communication. In contrast, transcript distribution in rodent brain shows no region-specific enrichment. As humans with CNTNAP2 mutations exhibit features of ASD and SLI, we will develop small hairpin RNA constructs that decrease Cntnap2 levels, first in cultures of zebra finch telencephalic neurons, then in ovo in the developing embryo. We will determine the effects of Cntnap2 reduction on electrophysiological and neuroanatomical properties in vitro and in vivo, and on vocal learning, other social and repetitive behaviors. Not only will this work illuminate Cntnap2's role in ASD, it will additionally provide a proof-of- principle for use of songbirds in understanding the role of other autism susceptibility genes on socially-learned vocal communication. A songbird model of ASD promises to provide critical information about cellular and circuit effects, and will be useful for screening therapeutic interventions. Our studies aim to inform novel approaches to improve social interactions, and thus the quality of life, of autistic children. PUBLIC HEALTH RELEVANCE: Children diagnosed with autism fail to develop language, have other social difficulties and overly repetitive behaviors. To understand the neural basis for these deficits, we will develop a novel model of autism using songbirds, arguably the only practical laboratory model for probing the vocal learning subcomponent of language. We will investigate the role of the autism susceptibility gene, Cntnap2, on vocal learning and other social and repetitive behaviors, with the goal of applying these findings to humans and formulating novel approaches to improve social interactions, speech learning, and the quality of life of autistic children.