Astrocytes release ATP/ADP and glutamate in flashes via vesicular exocytosis

Heng Li; Yuqing Zhao; Ruicheng Dai; Peiyao Geng; Danwei Weng; Wenting Wu; Fengting Yu; Rui Lin; Zhaofa Wu; Yulong Li; Minmin Luo

doi:10.1038/s41380-024-02851-8

Astrocytes release ATP/ADP and glutamate in flashes via vesicular exocytosis

Mol Psychiatry. 2024 Nov 22. doi: 10.1038/s41380-024-02851-8. Online ahead of print.

Authors

Heng Li^{1

2

3}, Yuqing Zhao¹, Ruicheng Dai⁴, Peiyao Geng^{1

3}, Danwei Weng¹, Wenting Wu^{1

3}, Fengting Yu⁴, Rui Lin^{1

3}, Zhaofa Wu⁵, Yulong Li^{6

7}, Minmin Luo^{8

9

10

11}

Affiliations

¹ National Institute of Biological Sciences (NIBS), Beijing, 102206, Beijing, China.
² School of Life Sciences, Tsinghua University, 100084, Beijing, China.
³ Tsinghua Institute of Multidisciplinary Biomedical Research (TIMBR), 102206, Beijing, China.
⁴ Chinese Institute for Brain Research (CIBR), Beijing, 102206, Beijing, China.
⁵ State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101, Beijing, China.
⁶ State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, 100871, Beijing, China.
⁷ New Cornerstone Science Laboratory, 518054, Shenzhen, China.
⁸ Chinese Institute for Brain Research (CIBR), Beijing, 102206, Beijing, China. luominmin@cibr.ac.cn.
⁹ New Cornerstone Science Laboratory, 518054, Shenzhen, China. luominmin@cibr.ac.cn.
¹⁰ Research Unit of Medical Neurobiology, Chinese Academy of Medical Sciences, 100005, Beijing, China. luominmin@cibr.ac.cn.
¹¹ Beijing Institute for Brain Research, Chinese Academy of Medical Sciences & Peking Union Medical College, 102206, Beijing, China. luominmin@cibr.ac.cn.

PMID: 39578520
DOI: 10.1038/s41380-024-02851-8

Abstract

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 Ca²⁺ 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 Ca²⁺-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.