Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice.
Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice.
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DOI：
10.1038/ncomms12627
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发表时间：
2016-09-01
影响因子：
16.6
通讯作者：
De Zeeuw CI
中科院分区：
文献类型：
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作者：
Peter S;Ten Brinke MM;Stedehouder J;Reinelt CM;Wu B;Zhou H;Zhou K;Boele HJ;Kushner SA;Lee MG;Schmeisser MJ;Boeckers TM;Schonewille M;Hoebeek FE;De Zeeuw CI
编码突触后支架蛋白SHANK2的基因中的功能缺失突变是涉及小脑相关运动问题的自闭症谱系障碍（ASD）的高度渗透性原因。最近的研究表明小脑病理学与ASD的病因有关。在这里，我们评估的可能性，小脑浦肯野细胞（PC）的ASD样病理生理学在小鼠缺乏Shank2的一个关键位点。Shank2的缺失损害PC内在可塑性和在平行纤维到PC突触的长时程增强的诱导。此外，抑制输入到PC显着增强，最突出的是在后叶的简单穗（SS）的规律性是最受影响的。使用PC特异性Shank2基因敲除，我们在体内复制了SS规律性的改变，并在运动学习和社会互动中建立了ASD样行为表型的小脑依赖性。这些数据突出了Shank2对PC功能的重要性，并支持小脑病理在某些形式的ASD中突出的模型。 SHANK2的突变与自闭症谱系障碍（ASD）有关。在这里，Peter等人表明，小鼠小脑浦肯野细胞中Shank2的选择性缺失导致可塑性、运动行为和类似于ASD中所见的社会行为表型的缺陷。
Loss-of-function mutations in the gene encoding the postsynaptic scaffolding protein SHANK2 are a highly penetrant cause of autism spectrum disorders (ASD) involving cerebellum-related motor problems. Recent studies have implicated cerebellar pathology in the aetiology of ASD. Here we evaluate the possibility that cerebellar Purkinje cells (PCs) represent a critical locus of ASD-like pathophysiology in mice lacking Shank2. Absence of Shank2 impairs both PC intrinsic plasticity and induction of long-term potentiation at the parallel fibre to PC synapse. Moreover, inhibitory input onto PCs is significantly enhanced, most prominently in the posterior lobe where simple spike (SS) regularity is most affected. Using PC-specific Shank2 knockouts, we replicate alterations of SS regularity in vivo and establish cerebellar dependence of ASD-like behavioural phenotypes in motor learning and social interaction. These data highlight the importance of Shank2 for PC function, and support a model by which cerebellar pathology is prominent in certain forms of ASD. Mutations in SHANK2 are associated with autism spectrum disorders (ASD). Here, Peter et al. show that selective loss of Shank2 in Purkinje cells of the mouse cerebellum leads to deficits in plasticity, motor behaviour, and a social behaviour phenotype similar to that seen in ASD.