Chronic stress is one of the most potent risk factors for the onset of major depressive disorder. Chronic unpredictable mild stress results in reduced 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 our research, 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 depression- and anxiety-like behavioral effects of chronic stress in mice. Notably, Ppp4r3a deficiency led to down-regulated mTORC1 signaling, which resulted in reduced synthesis of synaptic proteins and impaired synaptic functions. On the contrary, 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 revealed a regulatory role of Ppp4r3a in driving synaptic protein synthesis in chronic stress.

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