Cerebellar Shank2 Regulates Excitatory Synapse Density, Motor Coordination, and Specific Repetitive and Anxiety-Like Behaviors
Cerebellar Shank2 Regulates Excitatory Synapse Density, Motor Coordination, and Specific Repetitive and Anxiety-Like Behaviors
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DOI：
10.1523/jneurosci.1849-16.2016
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发表时间：
2016-11-30
影响因子：
5.3
通讯作者：
Kim, Eunjoon
中科院分区：
文献类型：
--
作者：
Ha, Seungmin;Lee, Dongwon;Kim, Eunjoon
Shank 2是一种多结构域支架蛋白，参与兴奋性突触后位点多蛋白复合物的结构和功能协调以及精神障碍，包括自闭症谱系障碍。虽然Shank 2在小脑中强烈表达，但Shank 2是否调节小脑兴奋性突触，或有助于在Shank 2（-/-）小鼠中观察到的行为异常，仍然未被探索。在这里，我们表明，Shank 2（-/-）小鼠显示小脑浦肯野细胞的兴奋性突触密度降低，与兴奋性突触后蛋白，包括谷氨酸D2和PSD-93的水平降低，并在伊拉斯谟测试受损的运动协调。仅限于浦肯野细胞的Shank 2缺失（Pcp 2-Cre; Shank 2（fl/fl）小鼠）导致兴奋性突触密度、突触蛋白水平和运动协调的类似降低。Pcp2-Cre; Shank 2（fl/fl）小鼠不重现在Shank 2（-/-）小鼠中观察到的自闭症样行为，如社交互动缺陷、改变的超声发声、重复行为和多动。然而，Pcp 2-Cre; Shank 2（fl/fl）小鼠在洞板测试中表现出增强的重复行为，在光暗测试中表现出焦虑样行为，这在Shan 2（-/-）小鼠中未观察到。这些结果表明Shank 2参与了小脑兴奋性突触密度、运动协调以及特定重复和焦虑样行为的调节。
Shank2 is a multidomain scaffolding protein implicated in the structural and functional coordination of multiprotein complexes at excitatory postsynaptic sites as well as in psychiatric disorders, including autism spectrum disorders. While Shank2 is strongly expressed in the cerebellum, whether Shank2 regulates cerebellar excitatory synapses, or contributes to the behavioral abnormalities observed in Shank2(-/-) mice, remains unexplored. Here we show that Shank2(-/-) mice show reduced excitatory synapse density in cerebellar Purkinje cells in association with reduced levels of excitatory postsynaptic proteins, including GluD2 and PSD-93, and impaired motor coordination in the Erasmus test. Shank2 deletion restricted to Purkinje cells (Pcp2-Cre; Shank2(fl/fl) mice) leads to similar reductions in excitatory synapse density, synaptic protein levels, and motor coordination. Pcp2-Cre; Shank2(fl/fl) mice do not recapitulate autistic-like behaviors observed in Shank2(-/-) mice, such as social interaction deficits, altered ultrasonic vocalizations, repetitive behaviors, and hyperactivity. However, Pcp2-Cre; Shank2(fl/fl) mice display enhanced repetitive behavior in the hole-board test and anxiety-like behavior in the light-dark test, which are not observed in Shan2(-/-) mice. These results implicate Shank2 in the regulation of cerebellar excitatory synapse density, motor coordination, and specific repetitive and anxiety-like behaviors.