Department of Neurology, Department of Neurobiology and Department of Rehabilitation, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China.
Department of Critical Care Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310030, China.
Neurobiol Dis. 2023 Oct 1;186:106273. doi: 10.1016/j.nbd.2023.106273. Epub 2023 Aug 28.
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.
癫痫是最常见的神经障碍之一。涉及小胶质细胞和星形胶质细胞激活的神经炎症是癫痫发生的一个重要且常见的机制。瞬时受体电位 melastatin 2（TRPM2）是一种钙通透性、非选择性阳离子通道，在各种与炎症相关的疾病中发挥病理性作用。我们之前的研究表明，Trpm2 敲除在匹罗卡品诱导的胶质细胞激活和神经炎症中具有治疗作用。然而，小胶质细胞和星形胶质细胞中的 TRPM2 是否在这个过程中发挥共同的致病作用及其潜在的分子机制尚不清楚。在这里，我们证明了小胶质细胞 TRPM2 在癫痫发生中的一个以前未知的作用。小胶质细胞中的 Trpm2 敲除减轻了红藻氨酸（KA）诱导的胶质细胞激活、炎症细胞因子的产生和海马阵发性放电，而星形胶质细胞中的 Trpm2 敲除则没有明显的作用。此外，我们发现这些治疗作用是通过小胶质细胞中腺苷一磷酸激活蛋白激酶（AMPK）/雷帕霉素靶蛋白（mTOR）途径上调自噬介导的。因此，我们的研究结果强调了小胶质细胞 TRPM2 在颞叶癫痫中的重要有害作用。
