Wang Xiaoya, Xu Man, Xu Qingbao, Yang Feng, Tang Hui, Shao Chuan, Wang Luyi, Wang Yan, Deng Jing, Wang Shali
Cerebrovascular Disease Laboratory, Institute of Neuroscience, Chongqing Medical University, 400016 Chongqing, China.
Department of Physiology, School of Basic Medical Sciences, Chongqing Medical University, 400016 Chongqing, China.
Front Biosci (Landmark Ed). 2021 Aug 30;26(8):335-346. doi: 10.52586/4947.
: The gene which encodes a δ-catenin protein (CTNND2) is associated with multiple severe neurological disorders. However, the specific role of in spatial cognition and related mechanisms remains obscure. : In this study, we generated a new line of -Knock out (KO) mice with its exon2 deleted, and then characterized their behavioral phenotypes and explore the Biological mechanism. : -KO mice were with typical autism-like behaviors as evidenced by reduced social interaction in three-chamber sociability test, more frequent stereotypic behaviors (self-grooming), and deficits in spatial learning and memory tested by the Morris water maze. Furthermore, the expression of Rictor protein, a core component of the mTORC2 complex, was significantly decreased in the hippocampus of mutant mice. ShRNA-induced knockdown of Rictor protein in the hippocampus of both -KO mice and wild-type mice exacerbated spatial learning and memory deficits but did not affect their autism-like behaviors. Mechanistically, the hippocampal CA1 neurons of -KO mice showed decreased actin polymerization, postsynaptic spine density. Down-regulation of Rictor resulted in altered expression of post-synaptic proteins such as GluR1 and ELKS, but not presynaptic protein Synapsin1, implying abnormal synaptic changes in KO mice. : The gene is involved in spatial learning and memory via Rictor-mediated actin polymerization and synaptic plasticity. Our study provides a novel insight into the role and mechanisms of the gene in cognition at the molecular and synaptic levels.
编码δ-连环蛋白（CTNND2）的基因与多种严重神经疾病相关。然而，其在空间认知中的具体作用及相关机制仍不清楚。在本研究中，我们构建了一个外显子2缺失的新的δ-连环蛋白基因敲除（KO）小鼠品系，然后对其行为表型进行了表征并探究其生物学机制。δ-连环蛋白基因敲除小鼠表现出典型的自闭症样行为，三室社交试验中社交互动减少、刻板行为（自我梳理）更频繁，以及通过莫里斯水迷宫测试发现空间学习和记忆存在缺陷，均证明了这一点。此外，mTORC2复合物的核心成分Rictor蛋白在突变小鼠海马体中的表达显著降低。在δ-连环蛋白基因敲除小鼠和野生型小鼠的海马体中，通过短发夹RNA诱导敲低Rictor蛋白会加剧空间学习和记忆缺陷，但不影响它们的自闭症样行为。从机制上讲，δ-连环蛋白基因敲除小鼠的海马CA1神经元表现出肌动蛋白聚合减少、突触后棘密度降低。Rictor的下调导致突触后蛋白如GluR1和ELKS的表达改变，但不影响突触前蛋白突触素1，这意味着基因敲除小鼠存在异常的突触变化。δ-连环蛋白基因通过Rictor介导的肌动蛋白聚合和突触可塑性参与空间学习和记忆。我们的研究在分子和突触水平上为δ-连环蛋白基因在认知中的作用和机制提供了新的见解。
