Ppp4r3a deficiency leads to depression-like behaviors in mice by modulating the synthesis of synaptic proteins.
Ppp4r3a deficiency leads to depression-like behaviors in mice by modulating the synthesis of synaptic proteins.
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Ppp4r3a 缺陷通过调节突触蛋白的合成导致小鼠抑郁样行为
DOI：
10.1242/dmm.049374
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发表时间：
2022-06-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
慢性应激是严重抑郁障碍发病的主要危险因素之一。在啮齿动物模型中，慢性不可预测的温和应激导致突触蛋白表达减少和抑郁样行为。然而，感觉对突触蛋白的需求并在慢性应激下启动其合成的上游分子仍然未知。在本研究中，慢性不可预测的温和应激降低了小鼠前额叶皮质和海马区PPP4R3A的表达。大脑皮质和海马区Ppp4r3a的选择性敲除模拟了慢性应激对小鼠抑郁和焦虑的行为影响。值得注意的是，Ppp4r3a缺乏导致mTORC1信号下调，导致突触蛋白合成减少，突触功能受损。相比之下，Ppp4R3a在皮质和海马区的过表达以PPP4R3A-mTORC1依赖的方式保护动物免受慢性应激诱导的行为和突触缺陷。雷帕霉素处理过表达Ppp4r3a的神经元，通过直接抑制mTORC1，阻断了Ppp4r3a对突触蛋白合成的调节作用。总体而言，我们的结果揭示了Ppp4r3a在慢性应激中驱动突触蛋白质合成的调节作用。摘要：慢性不可预测的温和应激，一种可能的抑郁症模型，降低了小鼠PPP4R3A的表达。PPP4R3A缺陷小鼠通过抑制mTORC1介导的突触蛋白的合成而导致抑郁样行为。
Chronic stress is one of the main risk factors for the onset of major depressive disorder. Chronic unpredictable mild stress results in reduced expression of synaptic proteins and depression-like behaviors in rodent models. However, the upstream molecule that senses the demand for synaptic proteins and initiates their synthesis under chronic stress remains unknown. In this study, chronic unpredictable mild stress reduced the expression of PPP4R3A in the prefrontal cortex and hippocampus in mice. Selective knockout of Ppp4r3a in the cortex and hippocampus mimicked the depression- and anxiety-like behavioral effects of chronic stress in mice. Notably, Ppp4r3a deficiency led to downregulated mTORC1 signaling, which resulted in reduced synthesis of synaptic proteins and impaired synaptic functions. By contrast, overexpression of Ppp4r3a in the cortex and hippocampus protected against behavioral and synaptic deficits induced by chronic stress in a PPP4R3A–mTORC1-dependent manner. Rapamycin treatment of Ppp4r3a-overexpressing neurons blocked the regulatory effect of Ppp4r3a on the synthesis of synaptic proteins by directly inhibiting mTORC1. Overall, our results reveal a regulatory role of Ppp4r3a in driving synaptic protein synthesis in chronic stress. Summary: Chronic unpredictable mild stress, a putative model of depression, reduced PPP4R3A expression in mice. PPP4R3A deficiency in mice leads to depression-like behaviors by inhibiting mTORC1-mediated synthesis of synaptic proteins.
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影响因子：
6.1
作者：
Joshi S;Sun H;Rajasekaran K;Williamson J;Perez-Reyes E;Kapur J
通讯作者：
Kapur J
DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
影响因子：
4.8
作者：
Dong, Seung Myung;Byun, Hyun-Jung;Rho, Seung Bae
通讯作者：
Rho, Seung Bae
影响因子：
7.2
作者：
Byun, Hyun-Jung;Kim, Boh-Ram;Rho, Seung Bae
通讯作者：
Rho, Seung Bae
影响因子：
5.1
作者：
de Bartolomeis, Andrea;Latte, Gianmarco;Iasevoli, Felice
通讯作者：
Iasevoli, Felice