Li Heng, Zhao Yuqing, Dai Ruicheng, Geng Peiyao, Weng Danwei, Wu Wenting, Yu Fengting, Lin Rui, Wu Zhaofa, Li Yulong, Luo Minmin
National Institute of Biological Sciences (NIBS), Beijing, 102206, Beijing, China.
School of Life Sciences, Tsinghua University, 100084, Beijing, China.
Mol Psychiatry. 2025 Jun;30(6):2475-2489. doi: 10.1038/s41380-024-02851-8. Epub 2024 Nov 22.
Astrocytes regulate brain functions through gliotransmitters like ATP/ADP and glutamate, but their release patterns and mechanisms remain controversial. Here, we visualized ATP/ADP and glutamate response following astrocyte activation and investigated their mechanisms in vivo. Employing cOpn5-mediated optogenetic stimulation, genetically encoded fluorescent sensors, and two-photon imaging, we observed ATP/ADP released as temporally prolonged and spatially extended flashes that later converted to adenosine. This release occurs via Ca and VNUT-dependent vesicular exocytosis. Additionally, astrocytes also release glutamate in flashes through TeNT-sensitive exocytosis, independent of ATP/ADP release. ATP/ADP released by astrocytes triggers further ATP/ADP release from microglia through P2Y12- and VNUT-dependent mechanisms. VNUT in astrocytes and microglia also contributes to ATP/ADP release under LPS-induced brain inflammation. These findings establish Ca-dependent vesicular exocytosis as a key mode of action, reveal intricate astrocyte-microglia interactions, and suggest a role for gliotransmission in brain inflammation. Furthermore, the methodologies may provide valuable tools for deciphering glial physiology and pathophysiology.
星形胶质细胞通过三磷酸腺苷/二磷酸腺苷（ATP/ADP）和谷氨酸等神经胶质递质调节脑功能，但其释放模式和机制仍存在争议。在此，我们观察了星形胶质细胞激活后ATP/ADP和谷氨酸的反应，并在体内研究了它们的机制。利用环化视蛋白5（cOpn5）介导的光遗传学刺激、基因编码荧光传感器和双光子成像，我们观察到ATP/ADP以时间上延长、空间上扩展的闪光形式释放，随后转化为腺苷。这种释放通过钙（Ca）和囊泡核苷酸转运体（VNUT）依赖性囊泡胞吐作用发生。此外，星形胶质细胞还通过破伤风毒素（TeNT）敏感的胞吐作用以闪光形式释放谷氨酸，这一过程独立于ATP/ADP的释放。星形胶质细胞释放的ATP/ADP通过P2Y12和VNUT依赖性机制触发小胶质细胞进一步释放ATP/ADP。星形胶质细胞和小胶质细胞中的VNUT在脂多糖（LPS）诱导的脑部炎症下也有助于ATP/ADP的释放。这些发现确立了钙依赖性囊泡胞吐作用作为关键作用模式，揭示了星形胶质细胞与小胶质细胞之间复杂的相互作用，并提示神经胶质传递在脑部炎症中发挥作用。此外，这些方法可能为解读神经胶质细胞的生理和病理生理学提供有价值的工具。
