Abstract: Objective To explore the role of proton-sensitive G protein-coupled receptor GPR68 in the pathogenesis of depression and provide a new potential target for clinical treatment.Methods A chronic social defeat stress (CSDS) mouse model of depression was established. Behavioral changes were assessed using the forced swim test, tail suspension test, sucrose preference test, and social interaction test. GPR68 agonist Ogerin (2.5 mg/kg) was administered through intraperitoneal injection. The levels of GPR68 and proteins in the CREB/BDNF signaling pathway in mouse hippocampal tissue were detected by Western blot. The levels of inflammatory cytokines and neurotransmitters in serum and hippocampal tissue were measured by ELISA. Hippocampal neurogenesis in each group was observed by immunofluorescence staining.Results Compared with the control group, mice in the CSDS model group exhibited significant depressive-like behaviors, decreased protein levels of GPR68 and the CREB/BDNF signaling pathway, increased pro-inflammatory cytokines, and reduced neurogenesis (P<0.01). Ogerin treatment reversed these changes, improved depressive-like behaviors, upregulated the levels of the GPR68 and the CREB/BDNF signaling pathway (P<0.01), reduced pro-inflammatory cytokines and microglia-specific marker IBA-1 expression (P<0.01), and increased the number of DCX-positive cells in the hippocampus (P<0.01).Conclusions GPR68 promotes hippocampal neurogenesis and inhibits neuroinflammation by activating the CREB/BDNF signaling pathway, thereby improving depressive-like behaviors induced by CSDS in mice.