Hippocampal REDD1 inhibition is critical for alleviating depressive-like behaviors.

Depression is characterized by distinct pathological and synaptic abnormalities in the hippocampus; however, the underlying mechanisms remain poorly understood. We demonstrate for the first time that Regulated in development and DNA damage response-1 (REDD1) is upregulated in hippocampal neurons in three depression models induced by typical stressors. Notably, the hippocampus is the only brain region where REDD1 is highly expressed-this effect is not observed in the hypothalamus, prefrontal cortex, nucleus accumbens, or dorsal raphe. Downregulation of REDD1 effectively rescued depressive-like behaviors in chronic social defeat stress (CSDS) model mice, activated mTORC1 in hippocampal neurons, and reduced synaptic loss, while overexpression of REDD1 specifically in hippocampal neurons triggered depressive-like behaviors in non-stressed mice. These findings were further validated using REDD1 knockdown and mTORC1 inhibition models. Moreover, a novel compound, X837, potently inhibited REDD1, leading to rapid alleviation of depression-like behaviors, robust activation of the mTORC1 pathway, and restoration of synaptic deficits. The antidepressant effects of X837 were dependent on the REDD1/mTORC1 axis in hippocampal neurons. In conclusion, REDD1 in hippocampal neurons is a potent antidepressant target which functions via the mTORC1 signaling pathway. Interfering with REDD1 is a potential target to rescue depressive-like behaviors.