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.