Rendall Amanda R, Perrino Peter A, Buscarello Alexzandrea N, Fitch R Holly
Yale University School of Medicine, Pediatrics, 464 Congress Ave, New Haven, 06520-8055, CT, USA; University of Connecticut, Psychology-Behavioral Neuroscience, 406 Babbidge Road, Unit 1020 Storrs, 06269, CT, USA.
University of Connecticut, Psychology-Behavioral Neuroscience, 406 Babbidge Road, Unit 1020 Storrs, 06269, CT, USA.
Int J Dev Neurosci. 2019 Feb;72:13-21. doi: 10.1016/j.ijdevneu.2018.10.003. Epub 2018 Oct 29.
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a core set of atypical behaviors in social-communicative and repetitive-motor domains. Individual profiles are widely heterogeneous and include language skills ranging from nonverbal to hyperlexic. The causal mechanisms underlying ASD remain poorly understood but appear to include a complex combination of polygenic and environmental risk factors. SHANK3 (SH3 and multiple ankyrin repeat domains 3) is one of a subset of well-replicated ASD-risk genes (i.e., genes demonstrating ASD associations in multiple studies), with haploinsufficiency of SHANK3 following deletion or de novo mutation seen in about 1% of non-syndromic ASD. SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses. In order to more closely evaluate the contribution of SHANK3 to neurodevelopmental expression of ASD, a knockout mouse model with a mutation in the PDZ domain was developed. Initial research showed compulsive/repetitive behaviors and impaired social interactions in these mice, replicating two core ASD features. The current study was designed to further examine Shank3B heterozygous and homozygous knockout mice for behaviors that might map onto atypical language in ASD (e.g., auditory processing, and learning/memory). We report findings of repetitive and atypical aggressive social behaviors (replicating prior reports), novel evidence that Shank3B KO mice have atypical auditory processing (low-level enhancements that might have a direct relationship with heightened pitch discrimination seen in ASD), as well as robust learning impairments.
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征是在社交沟通和重复运动领域存在一系列典型行为。个体表现差异很大，包括从非语言到词汇超常的语言技能。ASD的潜在因果机制仍知之甚少，但似乎包括多基因和环境风险因素的复杂组合。SHANK3（SH3和多个锚蛋白重复结构域3）是一组经过充分验证的ASD风险基因中的一个（即，在多项研究中显示与ASD相关的基因），约1%的非综合征性ASD患者中可见SHANK3基因缺失或新发突变导致的单倍体不足。SHANK3是一种突触支架蛋白，在兴奋性突触的突触后致密区富集。为了更密切地评估SHANK3对ASD神经发育表达的贡献，构建了一种在PDZ结构域有突变的基因敲除小鼠模型。初步研究表明，这些小鼠存在强迫性/重复性行为和社交互动受损，重现了ASD的两个核心特征。本研究旨在进一步检查Shank3B杂合子和纯合子基因敲除小鼠，以观察可能与ASD非典型语言相关的行为（如听觉处理和学习/记忆）。我们报告了重复性和非典型攻击性社交行为的研究结果（重现了先前的报告），新的证据表明Shank3B基因敲除小鼠存在非典型听觉处理（低水平增强可能与ASD中增强的音高辨别直接相关）以及严重的学习障碍。
