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Astrocyte morphological remodeling regulates consciousness state transitions induced by inhaled general anesthesia

Molecular Psychiatry volume 30, pages 4006–4022 (2025)Cite this article

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Abstract

General anesthetics (GAs) are conventionally thought to induce loss of consciousness (LOC) by acting on pre- and post-synaptic targets. However, the mechanism underlying the involvement of astrocytes in LOC remains unclear. Here we report that inhaled GAs cause reversible impairments in the fine processes of astrocytes within the somatosensory cortex, mediated by regulating the phosphorylation level of Ezrin, a protein critical for the fine morphology of astrocytes. Genetically deleting Ezrin or disrupting its phosphorylation was sufficient to decrease astrocyte-synapse interaction and enhance sensitivity to sevoflurane (Sevo) in vivo. Moreover, we show that disrupting astrocytic Ezrin phosphorylation boosted the inhibitory effect of Sevo on pyramidal neurons by enhancing tonic GABA and lowering excitability under anesthesia. Our work reveals previously unappreciated phosphorylation-dependent morphological dynamics, which enable astrocytes to regulate neuronal activity during the transition between two brain consciousness states.

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Fig. 1: Sevo anesthesia induces morphological deficits in astrocytes.
Fig. 2: Sevo anesthesia impairs astrocyte-synapse interactions.
Fig. 3: Sevo induces morphological deficits in astrocytic fine processes by inhibiting the phosphorylation of Ezrin.
Fig. 4: Conditional knock-out of astrocytic Ezrin disrupts astrocyte-synapse contact and increases the sensitivity to Sevo anesthesia in mice.
Fig. 5: Disrupting Ezrin phosphorylation was sufficient to decrease astrocyte-synapse contact and enhance sensitivity to Sevo in vivo with effect to GABAergic synaptic transmission.
Fig. 6: Disrupting astrocytic Ezrin phosphorylation enhanced the inhibition of glutamatergic neurons by Sevo.

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Acknowledgements

We are grateful to Xueke Tan and Xixia Li for helping with electron microscopy sample preparation and taking scanning/transmission electron microscopy images at the Center for Biological Imaging (CBI), Institute of Biophysics, Chinese Academy of Science. We are grateful to Dr. Zhian Hu, Dr. Liping Wang, Dr. Min Xu for helpful discussions and valuable comments.

Funding

This work was supported by the Natural Science Foundation of China (Grant no. 82001130 to JR, 81873808 to ZY, 82371281 to ZT, 82401506 to ZB), and partially funded by the Department of Science and Technology of Sichuan Province (22NSFSC2418 to ZB, 2025ZNSFSC1645 to SM) and the 1-3-5 Project for Disciplines of Excellence of West China Hospital of Sichuan University (ZYJC21034 to JR).

Author information

Author notes

  1. These authors contributed equally: Bin Zhou, Qingran Li, Mengchan Su.

Authors and Affiliations

  1. Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, China

    Bin Zhou, Qingran Li, Yuncheng Luo, Rong Luo, Yunqing Yu, Jiao Jiao, Cheng Zhou, Yunxia Zuo, Jin Liu, Tao Zhu & Ruotian Jiang

  2. Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, China

    Bin Zhou, Qingran Li, Mengchan Su, Ping Liao, Yuncheng Luo, Rong Luo, Yunqing Yu, Meiyan Luo, Jiao Jiao, Limei Yi, Jing Wang, Linghui Yang, Daqing Liao, Cheng Zhou, Yunxia Zuo, Jin Liu, Tao Zhu & Ruotian Jiang

  3. Department of Pain Management, West China Hospital, Sichuan University, Chengdu, 610041, China

    Mengchan Su & Hong Xiao

  4. Institute of Brain Science and Diseases, West China Hospital, Sichuan University, Chengdu, 610213, China

    Fan Lei, Xin Li & Xia Zhang

  5. Department of Neurology, West China Hospital, Sichuan University, Chengdu, 610041, China

    Xia Zhang

Authors
  1. Bin Zhou
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  2. Qingran Li
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  3. Mengchan Su
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  4. Ping Liao
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  5. Yuncheng Luo
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  6. Rong Luo
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  7. Yunqing Yu
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  8. Meiyan Luo
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  9. Fan Lei
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  10. Xin Li
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  11. Jiao Jiao
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  12. Limei Yi
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  13. Jing Wang
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  14. Linghui Yang
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  15. Daqing Liao
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  16. Cheng Zhou
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  17. Xia Zhang
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  18. Hong Xiao
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  19. Yunxia Zuo
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  20. Jin Liu
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  21. Tao Zhu
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  22. Ruotian Jiang
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Contributions

ZB: study investigation, data analysis, article writing, and funding acquisition; LQ: study investigation, data analysis and article writing; SM: study investigation, data analysis, article writing and funding acquisition. LP, LR, YY, LY, LM, LF, LX, JJ, YL, WJ, YL, LD: study investigation and data analysis. ZC, ZX, XH: study design. ZY, ZT, LJ: study design, supervision, funding acquisition, lab resource. JR: study design, supervision, article writing and editing, lab resource and funding acquisition.

Corresponding authors

Correspondence to Yunxia Zuo, Jin Liu, Tao Zhu or Ruotian Jiang.

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Competing interests

The authors declare no competing interests.

Ethics approval

All methods were performed in accordance with the relevant guidelines and regulations. All animal experiments and procedures were approved by the Animal Research Committee at the West China Hospital of Sichuan University (20220223103, 20230220023).

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Zhou, B., Li, Q., Su, M. et al. Astrocyte morphological remodeling regulates consciousness state transitions induced by inhaled general anesthesia. Mol Psychiatry 30, 4006–4022 (2025). https://doi.org/10.1038/s41380-025-02978-2

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