Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism.
Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism.
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DOI：
10.1038/ncomms11459
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发表时间：
2016-05-10
影响因子：
16.6
通讯作者：
Jiang YH
中科院分区：
文献类型：
--
作者：
Wang X;Bey AL;Katz BM;Badea A;Kim N;David LK;Duffney LJ;Kumar S;Mague SD;Hulbert SW;Dutta N;Hayrapetyan V;Yu C;Gaidis E;Zhao S;Ding JD;Xu Q;Chung L;Rodriguiz RM;Wang F;Weinberg RJ;Wetsel WC;Dzirasa K;Yin H;Jiang YH
人类神经影像学研究表明，异常的神经连接是自闭症谱系障碍（ASD）行为缺陷的基础，但ASD的分子和神经回路机制仍然难以捉摸。在这里，我们描述了一个自闭症相关的Shank 3基因的完全敲除小鼠模型，外显子4-22（Δe4-22）缺失。mGluR 5-Homer支架和mGluR 5介导的信号传导在纹状体神经元中选择性地改变。这些变化与纹状体突触功能紊乱、异常脑形态、异常结构连接和ASD样行为有关。在体内记录表明，皮质-纹状体-丘脑电路是紧张性过度活跃的突变体，但在社会行为变得活跃减退。在Δe4-22−/−小鼠中，mGluR 5活性的调控可不同程度地减弱过度梳理和工具性学习，并挽救受损的纹状体突触可塑性。这些发现表明，Shank 3的缺乏会损害mGluR 5-Homer支架，导致皮质-纹状体回路异常，这是学习和ASD样行为缺陷的基础。这些数据表明遗传，分子和电路机制之间的因果关系的ASD的病理生理学。 SHANK 3突变与自闭症谱系障碍有关，尽管其潜在机制仍不清楚。在这里，作者生成了一个完整的敲除Shank 3小鼠模型，识别了与受损的mGluR 5-Homer支架和异常的大脑连接相关的ASD样行为。
Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4–22 (Δe4–22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4–22−/− mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs. SHANK3 mutations have been linked to autism spectrum disorders, although the underlying mechanisms remain unclear. Here, the authors generate a complete knockout Shank3 mouse model, identifying ASD-like behaviours associated with impaired mGluR5-Homer scaffolding and abnormal brain connectivity.