Piochon Claire, Kloth Alexander D, Grasselli Giorgio, Titley Heather K, Nakayama Hisako, Hashimoto Kouichi, Wan Vivian, Simmons Dana H, Eissa Tahra, Nakatani Jin, Cherskov Adriana, Miyazaki Taisuke, Watanabe Masahiko, Takumi Toru, Kano Masanobu, Wang Samuel S-H, Hansel Christian
Department of Neurobiology, University of Chicago, Chicago, Illinois 60637, USA.
1] Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA [2] Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey 08544, USA.
Nat Commun. 2014 Nov 24;5:5586. doi: 10.1038/ncomms6586.
A common feature of autism spectrum disorder (ASD) is the impairment of motor control and learning, occurring in a majority of children with autism, consistent with perturbation in cerebellar function. Here we report alterations in motor behaviour and cerebellar synaptic plasticity in a mouse model (patDp/+) for the human 15q11-13 duplication, one of the most frequently observed genetic aberrations in autism. These mice show ASD-resembling social behaviour deficits. We find that in patDp/+ mice delay eyeblink conditioning--a form of cerebellum-dependent motor learning--is impaired, and observe deregulation of a putative cellular mechanism for motor learning, long-term depression (LTD) at parallel fibre-Purkinje cell synapses. Moreover, developmental elimination of surplus climbing fibres--a model for activity-dependent synaptic pruning--is impaired. These findings point to deficits in synaptic plasticity and pruning as potential causes for motor problems and abnormal circuit development in autism.
自闭症谱系障碍（ASD）的一个常见特征是运动控制和学习受损，大多数自闭症儿童都有这种情况，这与小脑功能紊乱一致。在此，我们报告了人类15q11 - 13重复的小鼠模型（patDp/+）中运动行为和小脑突触可塑性的改变，15q11 - 13重复是自闭症中最常观察到的遗传畸变之一。这些小鼠表现出类似ASD的社交行为缺陷。我们发现，在patDp/+小鼠中，延迟眨眼条件反射——一种依赖小脑的运动学习形式——受损，并观察到一种假定的运动学习细胞机制，即平行纤维 - 浦肯野细胞突触处的长时程抑制（LTD）失调。此外，多余攀爬纤维的发育性消除——一种依赖活动的突触修剪模型——也受损。这些发现表明，突触可塑性和修剪缺陷可能是自闭症中运动问题和异常神经回路发育的潜在原因。
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