Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Autism Res. 2020 Oct;13(10):1698-1717. doi: 10.1002/aur.2364. Epub 2020 Sep 11.
Autism spectrum disorder (ASD) is characterized by social interaction and communication impairments, as well as restrictive/repetitive patterns of behavior, interests or activities, which can coexist with intellectual disability and altered sensory processing. To study the mechanisms underlying these core features of ASD, preclinical research has developed animal models with manipulations in ASD-linked genes, such as CNTNAP2. In order to fully interpret the findings from mechanistic studies, the extent to which these models display behaviors consistent with ASD must be determined. Toward that goal, we conducted an investigation of the consequences of a functional loss of Cntnap2 on ASD-related behaviors by comparing the performance of rats with a homozygous or heterozygous knockout of Cntnap2 to their wildtype littermates across a comprehensive test battery. Cntnap2 rats showed deficits in sociability and social novelty, and they displayed repetitive circling and hyperlocomotion. Moreover, Cntnap2 rats demonstrated exaggerated acoustic startle responses, increased avoidance to sounds of moderate intensity, and a lack of rapid audiovisual temporal recalibration; indicating changes in sensory processing at both the pre-attentive and perceptual levels. Notably, sensory behaviors requiring learned associations did not reveal genotypic differences, whereas tasks relying on automatic/implicit behaviors did. Ultimately, because these collective alterations in social, stereotypic, and sensory behaviors are phenotypically similar to those reported in individuals with ASD, our results establish the Cntnap2 knockout rat model as an effective platform to study not only the molecular and cellular mechanisms associated with ASD, but also the complex relationship between altered sensory processing and other core ASD-related behaviors. LAY SUMMARY: Autism spectrum disorder (ASD) is characterized by social interaction differences, and restrictive/repetitive patterns of behavior. We studied the behavioral alterations caused by the loss of an autism-linked gene, Cntnap2, in the rat to determine how mutations in this gene contribute to autism-related behaviors. We show the loss of Cntnap2 leads to changes in social, stereotypic, and sensory behaviors, indicating this rat model can be used to better understand the brain changes underlying ASD. Autism Res 2020, 13: 1698-1717. © 2020 International Society for Autism Research and Wiley Periodicals LLC.
自闭症谱系障碍（ASD）的特征是社交互动和沟通障碍，以及行为、兴趣或活动的限制/重复模式，这些障碍可能与智力障碍和感觉处理改变并存。为了研究 ASD 的这些核心特征的机制，临床前研究已经开发了具有 ASD 相关基因（如 CNTNAP2）操作的动物模型。为了充分解释机制研究的结果，必须确定这些模型显示与 ASD 一致的行为的程度。为此，我们通过比较 Cntnap2 杂合或纯合敲除大鼠与野生型同窝仔鼠在综合测试组合中的表现，对 Cntnap2 功能丧失对 ASD 相关行为的后果进行了研究。Cntnap2 大鼠在社交和社交新颖性方面存在缺陷，它们表现出重复性转圈和过度活跃。此外，Cntnap2 大鼠表现出夸张的听觉惊跳反应、对中等强度声音的回避增加，以及快速视听时间校准的缺乏；表明在注意前和感知水平上都存在感觉处理的变化。值得注意的是，需要学习关联的感觉行为没有显示基因型差异，而依赖于自动/隐式行为的任务则显示出差异。最终，由于这些社交、刻板和感觉行为的集体改变在表型上与 ASD 患者报告的相似，我们的结果确立了 Cntnap2 敲除大鼠模型作为一种有效的平台，不仅可以研究与 ASD 相关的分子和细胞机制，还可以研究感觉处理改变与其他 ASD 相关行为之间的复杂关系。
