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

Molecular Psychiatry volume 30, pages 2475–2489 (2025)Cite this article

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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.

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Fig. 1: cOpn5 optogenetics elicits Ca2+ signals in cortical astrocytes and prompts ATP/ADP release.
Fig. 2: ATP/ADP release occurs via VNUT-dependent vesicular exocytosis.
Fig. 3: Astrocytes release glutamate through TeNT-sensitive exocytosis.
Fig. 4: Microglia amplify extracellular ATP/ADP signals by astrocytes.
Fig. 5: VNUT in astrocytes and microglia contributes to LPS-induced ATP/ADP release.

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Data availability

All data necessary to assess the conclusions in this manuscript are provided in the main text or the supplemental information. Any additional information is available from the corresponding authors upon request.

Code availability

All codes necessary to assess the conclusions in this manuscript are provided in the main text or the supplemental information. Any additional information is available from the corresponding authors upon request.

Materials availability

All unique reagents generated in this study are available from the lead contact upon reasonable request.

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Acknowledgements

We thank W Ge (CIBR, Beijing) for comments, T Gao (Southern Medical University, Guangzhou, China) for Aldh1l1-CreERT2 mice, M Jing and W Sun (CIBR, Beijing) for advice on imaging, and Vector Core, Laboratory Animal Resource Center (LARC), and Optical Imaging Core at CIBR for technical supports.

Funding

This work was supported by the China Brain Initiative Grants (STI2030-Major Projects 2021ZD0202803 to ML and STI2030-Major Projects 2022ZD0208300 to ZW), Research Unit of Medical Neurobiology at Chinese Academy of Medical Sciences (2019RU003 to ML), New Cornerstone Investigator Program (to ML and YL), National Key R&D Program of China (2022YFE0108700 to YL), and Beijing Municipal Government (to ML).

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Authors and Affiliations

  1. National Institute of Biological Sciences (NIBS), Beijing, 102206, Beijing, China

    Heng Li, Yuqing Zhao, Peiyao Geng, Danwei Weng, Wenting Wu & Rui Lin

  2. School of Life Sciences, Tsinghua University, 100084, Beijing, China

    Heng Li

  3. Tsinghua Institute of Multidisciplinary Biomedical Research (TIMBR), 102206, Beijing, China

    Heng Li, Peiyao Geng, Wenting Wu & Rui Lin

  4. Chinese Institute for Brain Research (CIBR), Beijing, 102206, Beijing, China

    Ruicheng Dai, Fengting Yu & Minmin Luo

  5. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101, Beijing, China

    Zhaofa Wu

  6. State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, 100871, Beijing, China

    Yulong Li

  7. New Cornerstone Science Laboratory, 518054, Shenzhen, China

    Yulong Li & Minmin Luo

  8. Research Unit of Medical Neurobiology, Chinese Academy of Medical Sciences, 100005, Beijing, China

    Minmin Luo

  9. Beijing Institute for Brain Research, Chinese Academy of Medical Sciences & Peking Union Medical College, 102206, Beijing, China

    Minmin Luo

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  1. Heng Li
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Contributions

HL and ML conceived the study. ML supervised the project. HL performed surgeries, imaging, immunostaining, smFISH, and data analysis. YZ helped to perform surgeries and process data. PG performed RT-qPCR. RD, DW, FY, WW, and RL contributed to plasmid cloning and AAV packaging. YL and ZW provided GRAB sensors and the VNUT floxed mouse line. HL drafted the figures. HL and ML wrote the manuscript with inputs from all authors.

Corresponding author

Correspondence to Minmin Luo.

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Li, H., Zhao, Y., Dai, R. et al. Astrocytes release ATP/ADP and glutamate in flashes via vesicular exocytosis. Mol Psychiatry 30, 2475–2489 (2025). https://doi.org/10.1038/s41380-024-02851-8

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