AbstractBackgroundQingyangshen (Cynanchum otophyllum C.K. Schneid) is a folk drug for treating depression and other mental disorders induced by social defeat stress. Neuroplasticity in the hippocampus is essential for the modulation of cognition and emotion, and its impairment may contribute to the development and progression of depression. Our previous studies have found that Qingyangshen glycosides (QYS) can improve depression‐like behavior in social failure mouse models, mainly through PGC‐1α/FNDC5/BDNF signaling pathways activation, but its effects and mechanisms on hippocampal neuroplasticity remain unknown.MethodsChronic social defeat stress (CSDS) was used to induce social defeat in mice. Morphological changes in the hippocampus were observed by H&E staining and Golgi staining. Immunofluorescence double staining was used to detect the expression of synaptophysin (SYN) and postsynaptic density protein‐95 (PSD‐95), while western blot was employed to evaluate PSD‐95, SYN, and doublecortin (DCX) proteins. The pathological processing of social defeat and the therapeutic effects of QYS on it was confirmed through behavioral assessment associated with morphologic observation.ResultsDuring the whole study, the sucrose preference indices and OFT activity time of CSDS mice were significantly decreased (p ≤ 0.05), and the tail suspension immobility time was significantly increased (p ≤ 0.05), suggesting that the mice had significant depressive symptoms. Treatment with QYS (25, 50, and 100 mg/kg) significantly alleviated depressive symptoms in CSDS mice, which was demonstrated by significantly (p ≤ 0.05 or p ≤ 0.01) reducing the duration of tail‐hanging immobility and increasing the tendency of sucrose preference indices and OFT activity time. QYS treatment also significantly increased the expression of DCX, PSD‐95, and SYN proteins, which play a crucial role in depression.ConclusionsQYS alleviated these symptoms by enhancing hippocampal neuroplasticity through upregulating the expression of synapse‐associated proteins (SAPs). The therapeutic mechanism of QYS may involve modulating the neuroplasticity of hippocampus neurons by altering the expression of SAPs.