Xu Yingwei, Ye Luyu, Li Zhisheng, Zhang Yi, Hua Ning, Wang Xiaojun, Lu Wangjialu, Xi Jing, Chen Liying, Xu Cenglin, Fang Jiajia, Luo Jianhong, Jiang Linhua, Han Feng, Chen Zhong, Wang Yi, Yang Wei
Institute of Pharmacology & Toxicology NHC and CAMS Key Laboratory of Medical Neurobiology College of Pharmaceutical Sciences School of Medicine Zhejiang University Hangzhou China.
Zhejiang Key Laboratory of Neuropsychopharmacology School of Pharmaceutical Sciences Zhejiang Chinese Medical University Hangzhou China.
MedComm (2020). 2025 Jul 14;6(8):e70271. doi: 10.1002/mco2.70271. eCollection 2025 Aug.
Epilepsy is one of the most common neurological disorders, characterized by the enhancement of neural excitability from a neurocentric perspective. Emerging evidence indicates that microglia play a pivotal role in the pathogenesis of epilepsy through complex and various mechanisms that is still not fully understood. In this study, we demonstrate that the deficiency of transient receptor potential melastatin 2 (TRPM2) channel, a calcium-permeable nonselective cation channel, significantly accelerates seizure development in multiple mouse seizure models, including MES- and pentylenetetrazole(PTZ)-induced seizure model, intrahippocampal KA model, hippocampal kindling model, without affecting seizure susceptibility in initial acute seizure. Notably, it is the deficiency of TRPM2 specifically in microglia, rather than in CaMKIIα excitatory neurons or PV interneurons, that primarily responsible for seizure development. Moreover, microglial TRPM2 deficiency increases the excitability of hippocampal pyramidal neurons by enhancing the AMPAR-mediated excitatory synaptic transmission independent of changes in the expression of inflammatory cytokines. These findings reveal a previously unrecognized, inflammation-independent mechanism by which microglial instead of neuronal TRPM2 channel contributes to seizure development, highlighting microglial TRPM2 as a novel potential therapeutic target for epilepsy by specifically targeting microglial TRPM2 channel.
癫痫是最常见的神经系统疾病之一，从神经中心的角度来看，其特征在于神经兴奋性增强。新出现的证据表明，小胶质细胞通过复杂且尚未完全了解的多种机制在癫痫发病机制中起关键作用。在本研究中，我们证明瞬时受体电位香草酸亚型2（TRPM2）通道（一种钙通透性非选择性阳离子通道）的缺失，在包括最大电休克（MES）和戊四氮（PTZ）诱导的癫痫模型、海马内注射谷氨酸（KA）模型、海马点燃模型在内的多种小鼠癫痫模型中显著加速癫痫发作的发展，而不影响初始急性发作时的癫痫易感性。值得注意的是，主要是小胶质细胞中特异性的TRPM2缺失，而非CaMKIIα兴奋性神经元或小清蛋白（PV）中间神经元中的TRPM2缺失，导致癫痫发作的发展。此外，小胶质细胞TRPM缺2失通过增强AMPA受体介导的兴奋性突触传递，而不依赖于炎性细胞因子表达的变化，增加了海马锥体神经元的兴奋性。这些发现揭示了一种以前未被认识的、不依赖炎症的机制，即小胶质细胞而非神经元的TRPM2通道促成癫痫发作的发展，突出了小胶质细胞TRPM2作为癫痫的一种新的潜在治疗靶点，通过特异性靶向小胶质细胞TRPM2通道。
