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Electroacupuncture decreases microglia-mediated synaptic engulfment to ameliorate CUMS-induced depressive-like
Lijuan Zhang1, Ting Wei2, Xuan Liu2
1Acupuncture and Tuina School/The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China; Acupuncture and Brain Science Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
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.
Insights
Electroacupuncture (EA) therapy alleviates depression by reducing excessive synaptic pruning by microglia. This effect is mediated through the TREM2/DAP12 signaling pathway in the medial prefrontal cortex.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Aberrant microglia-mediated synaptic engulfment is a key factor in depression.
- Electroacupuncture (EA) shows antidepressant effects, but its mechanisms are unclear.
- This study explores EA's impact on microglial synaptic pruning via the TREM2/DAP12 pathway in depression.
Purpose of the Study:
- To investigate if EA can mitigate depression induced by chronic unpredictable mild stress (CUMS).
- To determine if EA modulates microglial synaptic engulfment through the TREM2/DAP12 pathway.
- To elucidate the role of the TREM2/DAP12 pathway in EA's antidepressant effects.
Main Methods:
- Mice were subjected to CUMS followed by EA treatment.
- Behavioral tests (FST, SPT, TST, OFT, EPM) assessed depressive and anxiety-like behaviors.
- Microglial activity, synaptic integrity, and TREM2/DAP12 pathway expression were analyzed using immunofluorescence, RT-qPCR, and Western blotting. TREM2 knockout mice were used to confirm pathway involvement.
Main Results:
- EA treatment significantly improved depressive and anxiety-like behaviors in CUMS mice.
- EA suppressed CUMS-induced synaptic loss and abnormal microglial phagocytosis in the medial prefrontal cortex (mPFC).
- Disruption of the TREM2/DAP12 pathway in TREM2 knockout mice abolished EA's protective effects, confirming pathway mediation.
Conclusions:
- EA therapy effectively ameliorates depression and anxiety-like behaviors in a mouse model.
- EA exerts its therapeutic effects by inhibiting excessive microglial synaptic pruning in the mPFC.
- The TREM2/DAP12 signaling pathway is crucial for mediating EA's antidepressant actions.
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