Juvenile Shank3b deficient mice present with behavioral phenotype relevant to autism spectrum disorder
Juvenile Shank3b deficient mice present with behavioral phenotype relevant to autism spectrum disorder
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DOI：
10.1016/j.bbr.2018.08.005
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发表时间：
2019-01-01
影响因子：
2.7
通讯作者：
Ward, Monika A.
中科院分区：
文献类型：
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作者：
Balaan, Chantell;Corley, Michael J.;Ward, Monika A.
自闭症谱系障碍(ASD)是一种广泛性、多因素的神经发育障碍，根据沟通、社会交往和刻板印象/重复行为三个行为领域的缺陷诊断。Shank基因突变占临床ASD病例的-1%，其中Shank3是最常见的基因变异。除了维持突触和促进树突成熟外，Shank基因还编码主要的支架蛋白，在谷氨酸能突触的突触后密度中构建核心复合体。带有Shank3的PDZ结构域缺失的雄性小鼠(Shank3B，KO)此前被证明表现出类似ASD的行为表型，并报告了自我伤害、重复梳理和异常的社会互动。我们的目标是扩展这些先前的发现，并使用一套全面的高度详细的ASD相关行为分析，包括评估在关键发育日和雄性和雌性Shank3B KO小鼠进行的小鼠超声波通讯。我们证明了与ASD相关的行为，非典型的互惠社会互动和不分青红皂白的重复梳理，在Shank3B KO小鼠的幼年发育阶段是明显的。我们的发现强调了利用Shank突变模型来了解该基因在ASD病因学中的影响的重要性，这可能使未来的研究重点放在ASD的病因学基因-环境相互作用上。
Autism spectrum disorder (ASD) is a pervasive, multifactorial neurodevelopmental disorder diagnosed according to deficits in three behavioral domains: communication, social interaction, and stereotyped/repetitive behaviors. Mutations in Shank genes account for - 1% of clinical ASD cases with Shank3 being the most common gene variant. In addition to maintaining synapses and facilitating dendritic maturation, Shank genes encode master scaffolding proteins that build core complexes in the postsynaptic densities of glutamatergic synapses. Male mice with a deletion of the PDZ domain of Shank3 (Shank3B KO) were previously shown to display ASD-like behavioral phenotypes with reported self-injurious repetitive grooming and aberrant social interactions. Our goal was to extend these previous findings and use a comprehensive battery of highly detailed ASD-relevant behavioral assays including an assessment of mouse ultrasonic communication carried out on key developmental days and male and female Shank3B KO mice. We demonstrate that ASD-related behaviors, atypical reciprocal social interaction and indiscriminate repetitive grooming, are apparent in juvenile stages of development of Shank3B KO mice. Our findings underscore the importance of utilizing Shank mutant models to understand the impact of this gene in ASD etiology, whichmay enable future studies focusing on etiological gene-environment interactions in ASD.