Yang Tingting, Lin Zhenzhou, Yu Mingjia, Li Yongchuan, Chen Jiancong, Liu Yuanchi, Huang Kaibin, Pan Suyue
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Glia. 2025 Oct;73(10):2057-2076. doi: 10.1002/glia.70056. Epub 2025 Jul 9.
Status epilepticus (SE) is a severe condition that results in uncontrollable cerebral edema and cognitive dysfunction. Recent studies suggest that the localization of aquaporin-4 (AQP4) in astrocytic endfeet plays a crucial role in regulating blood-brain water transport and cell volume control, particularly along perivascular pathways. However, the signaling mechanisms underlying AQP4 localization remain poorly understood. In this study, we utilized the genetically encoded fluorescent calcium (Ca) indicator GCaMp6f to investigate Ca signals in astrocytic somata, processes, and endfeet during SE induction and observed enhanced Ca signals in both the somata and perivascular endfeet of astrocytes. We employed genetic knockout of TRPM4 (Trpm4 ) and glibenclamide treatment to explore the role of sulfonylurea receptor 1 transient receptor potential melastatin-4 (SUR1-TRPM4) channel in these Ca responses. Both approaches significantly suppressed the Ca signals in the astrocytic endfeet and reduced perivascular expression of the Ca-related signaling pathway sensor calmodulin (CaM). Furthermore, we found that AQP4 localization was no longer confined to the domains of astrocytic endfeet following SE. Inhibition of SUR1-TRPM4 through pharmacological blockade or gene deletion restored the subcellular localization of AQP4, reduced cerebral edema, and improved cognitive outcomes post-SE. Our findings suggest that SUR1-TRPM4 plays a pivotal role in regulating astrocytic Ca signals and mediating the aberrant expression and subcellular localization of astrocytic AQP4 along perivascular pathways. Together, these findings demonstrate a novel molecular mechanism underscoring SUR1-TRPM4 therapy in the treatment of SE characterized by dysregulated Ca signaling in astrocytic endfeet.
癫痫持续状态（SE）是一种严重病症，可导致无法控制的脑水肿和认知功能障碍。最近的研究表明，水通道蛋白4（AQP4）在星形胶质细胞终足中的定位在调节血脑水转运和细胞体积控制中起着关键作用，尤其是沿血管周围途径。然而，AQP4定位的信号传导机制仍知之甚少。在本研究中，我们利用基因编码的荧光钙（Ca）指示剂GCaMp6f来研究SE诱导期间星形胶质细胞胞体、突起和终足中的Ca信号，并观察到星形胶质细胞的胞体和血管周围终足中Ca信号增强。我们采用TRPM4基因敲除（Trpm4 ）和格列本脲处理来探讨磺脲类受体1瞬时受体电位褪黑素4（SUR1-TRPM4）通道在这些Ca反应中的作用。两种方法均显著抑制了星形胶质细胞终足中的Ca信号，并降低了Ca相关信号通路传感器钙调蛋白（CaM）的血管周围表达。此外，我们发现SE后AQP4的定位不再局限于星形胶质细胞终足区域。通过药理学阻断或基因缺失抑制SUR1-TRPM4可恢复AQP4的亚细胞定位，减轻脑水肿，并改善SE后的认知结果。我们的研究结果表明，SUR1-TRPM4在调节星形胶质细胞Ca信号以及介导星形胶质细胞AQP4沿血管周围途径的异常表达和亚细胞定位中起关键作用。总之，这些发现揭示了一种新的分子机制，强调了SUR1-TRPM4疗法在治疗以星形胶质细胞终足Ca信号失调为特征的SE中的作用。
