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Neuropeptide-mediated activation of astrocytes improves stress resilience in mice by modulating cortical neural synapses

Acta Pharmacologica Sinica volume 46, pages 867–879 (2025)Cite this article

Abstract

Astrocytes are known to modulate synaptogenesis or neuronal activities, thus participating in mental functions. It has been shown that astrocytes are involved in the antidepressant mechanism. In this study we investigated the potential hormonal mediator governing the astrocyte-neuron interplay for stress-coping behaviors. Mice were subjected to chronic restraint stress (CRS) for 14 days, and then brain tissue was harvested for analyses. We found that the expression of pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor PAC1 was significantly decreased in astrocytes of the prelimbic (PrL) cortex. By conducting a combination of genetics, in vivo imaging and behavioral assays we demonstrated that PAC1 in cortical astrocytes was necessary for maintaining normal resilience of mice against chronic environmental stress like restraint stress. Furthermore, we showed the enhancement of de novo cortical spine formation and synaptic activity under PACAP-mediated astrocytic activation possibly via the ATP release. The molecular mechanisms suggested that the vesicle homeostasis mediated by PACAP-PAC1 axis in astrocytes was involved in regulating synaptic functions. This study identifies a previously unrecognized route by which neuropeptide modulates cortical functions via local regulation of astrocytes.

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Fig. 1: Astrocytic deprivation of PACAP axis induces anxiety-like behaviors.
Fig. 2: PACAP modulates astrocytic structure and calcium transients.
Fig. 3: Astrocytic PAC1 receptor mediates neuronal activity and synaptogenesis.
Fig. 4: PACAP activated astrocytes and spinogenesis in CRS-treated mice.
Fig. 5: PACAP stimulates astrocytic release of ATP.
Fig. 6: ATP or its analogue relieves anxiety-like behaviors induced by astrocytic PAC1 receptor deficiency.
Fig. 7: PACAP modulated cellular vesicle of astrocytes.

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Acknowledgements

We thank Prof. Xiang-dong Sun for his help in the 2-photon imaging assays. This work was funded by STI2030-Major Projects (2022ZD0207600) to LZ, National Natural Science Foundation of China (U22A20301 to KFS), Guangdong Major Project of Basic and Applied Basic Research (2023B0303000004) to KFS and LZ, Guangdong Basic and Applied Basic Research Foundation (2023B1515040015) to LZ, Guangdong Special Support Program for Young Talented Researchers (2023TQ07A102) to LZ, Guangzhou Basic and Applied Basic Research Foundation (SL2023A03J00544, SL2024A04J00149) to LZ, The Fundamental Research Funds for the Central Universities (21624207) to LZ, and the Key Research and Development Plan of Ningxia (2022BEG01004) to KFS.

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Authors and Affiliations

  1. State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China

    Jing Cui, Xiao-ran Wang, Jie Yu, Bo-rui Zhang, Kwok-Fai So, Li Zhang & Ji-an Wei

  2. College of Life Science and Technology, Jinan University, Guangzhou, 510632, China

    Ya-fei Shi

  3. State Key Laboratory of Brain and Cognitive Science, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Kwok-Fai So

  4. Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao, 266114, China

    Kwok-Fai So & Li Zhang

  5. Center for Exercise and Brain Science, School of Psychology, Shanghai University of Sport, Shanghai, 200438, China

    Kwok-Fai So & Li Zhang

  6. The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, China

    Kwok-Fai So & Li Zhang

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  1. Jing Cui
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  2. Xiao-ran Wang
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Contributions

Conceptualization, JAW, and LZ; Methodology, JAW, JC, XRW, JY, and YFS; Validation, JAW and LZ; Formal analysis, JAW and BRZ; Investigation, JC, XRW, JY, YFS and BRZ.; Resources, JC. and XRW; Data Curation, JAW and LZ; Writing - Original Draft, JAW. and JC; Writing – Review & Editing, LZ and KFS; Visualization, JAW; Supervision, KFS and LZ; Project Administration, LZ; Funding Acquisition, LZ and KFS.

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Correspondence to Li Zhang or Ji-an Wei.

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Cui, J., Wang, Xr., Yu, J. et al. Neuropeptide-mediated activation of astrocytes improves stress resilience in mice by modulating cortical neural synapses. Acta Pharmacol Sin 46, 867–879 (2025). https://doi.org/10.1038/s41401-024-01420-7

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