Cntnap2 in a behavioral model of autism

描述(由申请人提供)：语言、社交和行为灵活性方面的障碍共同出现在幼儿身上，构成了自闭症谱系障碍(ASD)的特征。语言，以及自闭症，是人类独有的表型，但对其神经生理学和分子基础的研究需要动物模型。这项建议的长期目标是开发一种使用斑马雀鸣鸟的新型自闭症模型。虽然没有一个单一的模型可以捕捉到ASD的所有特征，但鸣禽是少数几个可以研究由习得的声音交流组成的语言子成分之一。这是因为鸣禽和人类一样，与传统的实验动物不同，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对自闭症易感基因--接触蛋白相关蛋白2(Cntnap2)在有声学习者和非学习者大脑中的表达模式的比较。在人类和雀类中，cntnap2在功能上为习得的语音交流指定的区域中丰富。相比之下，转录产物在啮齿类动物大脑中的分布没有显示出区域特异性的丰富。由于CNTNAP2突变的人类表现出ASD和SLI的特征，我们将开发能够降低cntnap2水平的小发夹RNA结构，首先是在斑马雀端脑神经元的培养中，然后是在发育中的胚胎的卵子中。我们将确定cntnap2的减少在体外和体内对电生理和神经解剖学特性的影响，以及对发声学习和其他社会和重复行为的影响。这项工作不仅将阐明cntnap2的S在自闭症中的作用，它还将为利用鸣禽了解其他自闭症易感基因在社会学习发声交流中的作用提供一个原则证明。ASD的鸣鸟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社会互动，从而提高自闭症儿童的生活质量。 公共卫生相关性：被诊断为自闭症的儿童不能发展语言，有其他社交困难和过度重复的行为。为了了解这些缺陷的神经基础，我们将利用鸣禽开发一个新的自闭症模型，这可能是唯一一个探索语言发声学习亚成分的实用实验室模型。我们将研究自闭症易感基因cntnap2在发声学习和其他社交和重复行为中的作用，目标是将这些发现应用于人类，并制定新的方法来改善自闭症儿童的社交互动、言语学习和生活质量。

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.