Trpm2 deficiency in microglia attenuates neuroinflammation during epileptogenesis by upregulating autophagy via the AMPK/mTOR pathway

• Published in: Neurobiology of disease Vol. 186; p. 106273
• Main Authors: Chen, Chen, Zhu, Tao, Gong, Lifen, Hu, Zhe, Wei, Hao, Fan, Jianchen, Lin, Donghui, Wang, Xiaojun, Xu, Junyu, Dong, Xinyan, Wang, Yifan, Xia, Ningxiao, Zeng, Linghui, Jiang, Peifang, Xie, Yicheng
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2023; Elsevier
• Subjects: AMPK/mTOR pathway; Astrocytes; Autophagy; Epileptogenesis; Microglia; Neuroinflammation; Transient receptor potential melastatin 2; Epileptogenesis; NO; pAst; TAM; RT; DG; Transient receptor potential melastatin 2; CNS; AMPK/mTOR pathway; IBA1; pMG; TLE; Autophagy; CD11b; GLAST; TRPM2; CA1; TRP; CA3; FBS; HPDs; KA; IHKA; mTOR; MG; WT; PBS; Ast; KO; Astrocytes; EEG; qRT-PCR; Neuroinflammation; CM; Ctrl; IL-1β; CQ; IL-6; Microglia; GFAP; TNF-α; AMPK; pNeu; SEM; CD45; SQSTM1; ELISA
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2023.106273

Epilepsy is one of the most common neurological disorders. Neuroinflammation involving the activation of microglia and astrocytes constitutes an important and common mechanism in epileptogenesis. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that plays pathological roles in various inflammation-related diseases. Our previous study demonstrated that Trpm2 knockout exhibits therapeutic effects on pilocarpine-induced glial activation and neuroinflammation. However, whether TRPM2 in microglia and astrocytes plays a common pathogenic role in this process and the underlying molecular mechanisms remained undetermined. Here, we demonstrate a previously unknown role for microglial TRPM2 in epileptogenesis. Trpm2 knockout in microglia attenuated kainic acid (KA)-induced glial activation, inflammatory cytokines production and hippocampal paroxysmal discharges, whereas Trpm2 knockout in astrocytes exhibited no significant effects. Furthermore, we discovered that these therapeutic effects were mediated by upregulated autophagy via the adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in microglia. Thus, our findings highlight an important deleterious role of microglial TRPM2 in temporal lobe epilepsy. •Trpm2 knockout in microglia rather than astrocytes attenuates neuroinflammation and epileptogenesis.•Trpm2 knockout in microglia suppresses glial activation and neuroinflammation by upregulating autophagy.•Trpm2 knockout in microglia upregulates autophagy and attenuates inflammation via recruitment of the AMPK/mTOR pathway.