Electroacupuncture decreases microglia-mediated synaptic engulfment to ameliorate CUMS-induced depressive-like behaviors in the mPFC.

Abstract

BACKGROUND: Aberrant microglia-mediated synaptic engulfment is implicated in depression pathogenesis. Although electroacupuncture (EA) demonstrates antidepressant efficacy, the potential mechanisms are not fully understood. We investigated whether EA attenuates chronic unpredictable mild stress (CUMS)-induced depression by modulating microglial engulfment of synapses via TREM2/DAP12 pathway. METHODS: Mice underwent 3-week CUMS followed by EA for another 3-week. EA was applied at Baihui (GV20) /Yintang (GV29). Depressive-like behaviors were assessed in the forced swimming test (FST), sucrose preference test (SPT), tail suspension test (TST). Anxiety-like behaviors were assessed by open field test (OFT) and elevated plus maze (EPM). Microglia phenotypes were evaluated using immunofluorescence (IF) staining and real-time quantitative PCR (RT-qPCR) in the medial prefrontal cortex (mPFC) of mice. Synaptic integrity was quantified by IF staining and Golgi staining. In some experiments, we used TREM2/mice to examine its involvement in the effects of EA. TREM2/DAP12 pathway expression was detected by IF staining, RT-qPCR and western blotting. RESULTS: EA treatment ameliorated depressive and anxiety-like behaviors in CUMS-exposed mice. Furthermore, EA attenuated CUMS-induced synaptic loss and suppressed abnormal microglial phagocytosis of synapses in the mPFC. We identified the TREM2/DAP12 signaling pathway as crucially involved in mediating these effects of EA on microglial activity. Critically, using TREM2/mice to disrupt TREM2/DAP12 signaling abolished EA's protective effects on inhibition microglial activation, reduced synaptic elimination, and rescue of CUMS-induced depressive-like behaviors. CONCLUSION: This study demonstrates that EA treatment exerts its therapeutic effects against depression by inhibiting microglial over-pruning synapses in mPFC via activating the TREM2/DAP12 signaling pathway.