Down-regulation of MST1 in hippocampus protects against stress-induced depression-like behaviours and synaptic plasticity impairments

Depression is a common mental disorder, and its main environmental risk factor is chronic stress. The activation of mammalian STE20-like kinase 1 (MST1), a key factor involved in the underlying pathophysiology of stress, can trigger synaptic plasticity impairment, neuronal dysfunction and neuroinflammation. However, it is unclear whether down-regulation of MST1 in the hippocampus protects against stress-induced behavioural dysfunctions. In this study, three mouse models were used to assess the role of MST1 in stress. Various behavioural tests, in vivo electrophysiological recordings, Western blotting, Golgi staining and immunofluorescence assay were used. The data showed that the level of phospho-MST1 (T183) was significantly increased in the hippocampus of mice subjected to chronic unpredictable mild stress (CUMS) and that mice with MST1 overexpression showed depression-like behaviours. Importantly, the impairment of cognitive functions and the hippocampal synaptic plasticity induced by CUMS were significantly improved by MST1 knockdown, suggesting that MST1 down-regulation effectively protected against stress-induced behavioural dysfunctions. Moreover, MST1 knockdown suppressed CUMS-induced microglial activation, reduced the abnormal expression of inflammatory cytokines and impeded the activation of p38, implying that the antidepressant-like effects of MST1 knockdown were associated with inhibiting the p38 pathway. These findings suggest that hippocampal MST1 is an essential regulator of stress, which can be an ideal target for the development of antidepressants in the future.