Enlarged dendritic spines and pronounced neophobia in mice lacking the PSD protein RICH2
Enlarged dendritic spines and pronounced neophobia in mice lacking the PSD protein RICH2
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DOI：
10.1186/s13041-016-0206-6
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发表时间：
2016-03-11
期刊：
影响因子：
3.6
通讯作者：
Grabrucker, Andreas M.
中科院分区：
文献类型：
--
作者：
Sarowar, Tasnuva;Grabrucker, Stefanie;Grabrucker, Andreas M.
背景：中枢神经系统中的大多数神经元通过被称为树突棘的富含肌动蛋白的小突起接受兴奋性输入。根据突触活动，棘可以经历快速的形态改变。这种机制与学习和记忆的形成有关，因为它最终改变突触后膜上受体和蛋白质的数量和分布，从而调节突触输入。rho家族gtpase通过与细胞骨架成分和脊柱间室内的几种信号通路相互作用，在调节脊柱可塑性方面发挥重要作用。Rho-GAP相互作用CIP4同源蛋白2/RICH2是调节小gtpase的Rho-GAP蛋白，在突触后密度被鉴定为支架蛋白SHANK3的相互作用伙伴。结果：在这里，我们描述了RICH2在一种新型小鼠模型中的缺失。我们的研究结果表明，RICH2 KO动物对新事物表现出选择性和高度显著的恐惧，增加了刻板印象行为以及运动学习障碍。我们发现海马和小脑的多个脊柱突触增加，同时受体组成和肌动蛋白聚合发生改变。此外，我们观察到RICH2的缺失导致体内突触RAC1的去抑制。结论：结果与报道的RAC1活性对活动依赖性脊柱扩大至关重要的作用一致。由于SHANK3突变已知是自闭症谱系（ASD）神经精神疾病的病因，突触部位的SHANK3/RICH2复合物的分解可能至少部分地导致ASD中脊柱的异常形成和可塑性。
Background: The majority of neurons within the central nervous system receive their excitatory inputs via small, actin-rich protrusions called dendritic spines. Spines can undergo rapid morphological alterations according to synaptic activity. This mechanism is implicated in learning and memory formation as it is ultimately altering the number and distribution of receptors and proteins at the post-synaptic membrane, thereby regulating synaptic input. The Rho-family GTPases play an important role in regulating this spine plasticity by the interaction with cytoskeletal components and several signaling pathways within the spine compartment. Rho-GAP interacting CIP4 homologue2/RICH2 is a Rho-GAP protein regulating small GTPases and was identified as an interaction partner of the scaffolding protein SHANK3 at post-synaptic densities.Results: Here, we characterize the loss of RICH2 in a novel mouse model. Our results show that RICH2 KO animals display a selective and highly significant fear of novel objects and increased stereotypic behavior as well as impairment of motor learning. We found an increase in multiple spine synapses in the hippocampus and cerebellum along with alterations in receptor composition and actin polymerization. Furthermore, we observed that the loss of RICH2 leads to a disinhibition of synaptic RAC1 in vivo.Conclusions: The results are in line with the reported role of RAC1 activity being essential for activity-dependent spine enlargement. Since SHANK3 mutations are known to be causative for neuropsychiatric diseases of the Autism Spectrum (ASD), a disintegrated SHANK3/RICH2 complex at synaptic sites might at least in part be responsible for abnormal spine formation and plasticity in ASDs.