Repetitive transcranial magnetic stimulation exerts anti-inflammatory effects via modulating glial activation in mice with chronic unpredictable mild stress-induced depression

Aims: Recently numerous studies have demonstrated that neuroinflammation plays a critical role in the pathogenesis of depression. Repetitive transcranial magnetic stimulation (rTMS) has been used to treat depression for years but its mechanism is not fully elucidated. The present study was designed to investigate whether rTMS could alleviate neuroglia-associated neuro-inflammatory process in mice models of depression. Methods: Mice were treated with chronic unpredictable mild stress (CUMS) to induce depression models and received four weeks of 15 Hz rTMS. Then the depression-like behaviors, microglia activation, the level of astrocytes, pro-inflammatory cytokines and inflammation-related signaling pathways were evaluated. Results: rTMS ameliorated depression-like behaviors in CUMS-treated mice. rTMS not only markedly alleviated the activation of microglia but induced a switch of microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype in the hippocampus and prefrontal cortex. Meanwhile, rTMS reversed the down-regulation of astrocytes and inhibited high levels of interleukin (IL)-6, IL-18 and tumor necrosis factoralpha (TNF-alpha) caused by CUMS in above regions. Moreover, we found that anti-inflammatory actions by rTMS were associated with the TLR4/NF-xB/NLRP3 signaling pathway. Conclusion: Collectively, our findings indicate that rTMS can exert anti-inflammatory actions in depression and provide new insights into the mechanism of rTMS in the treatment of depression.