Original Article

Calhm2 governs astrocytic ATP releasing in the development of depression-like behaviors

  • Molecular Psychiatry volume 23, pages 883891 (2018)
  • doi:10.1038/mp.2017.229
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Abstract

Extracellular ATP is a widespread cell-to-cell signaling molecule in the brain, where it functions as a neuromodulator by activating glia and neurons. Although ATP exerts multiple effects on synaptic plasticity and neuro-glia interactions, as well as in mood disorders, the source and regulation of ATP release remain to be elaborated. Here, we define Calhm2 as an ATP-releasing channel protein based on in vitro and in vivo models. Conventional knockout and conditional astrocyte knockout of Calhm2 both lead to significantly reduced ATP concentrations, loss of hippocampal spine number, neural dysfunction and depression-like behaviors in mice, which can be significantly rescued by ATP replenishment. Our findings identify Calhm2 as a critical ATP-releasing channel that modulates neural activity and as a potential risk factor of depression.

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Acknowledgements

We sincerely thank Dr. Xu Zhiheng (Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China) for advices about measuring neural dendritic spine density. We are grateful to Dr. Ji Guangju (Institute of Biophysics, Chinese Academy of Sciences, Beijing, China), Dr. Wang Yun (Neuroscience Research Institute, School of Basic Medical Science, Peking University, Beijing, China) and Dr. Zhao Yongfang (Institute of Biophysics, Chinese Academy of Sciences, Beijing, China) for helpful discussions and technical help. This work was supported by grants from the National Nature Science Foundation of China (Grant No. 81230026, 81125010, 81030025 and 81400987) and the Beijing Nature Science Foundation (7132147).

Author contributions

MJ, QX and YZ conceived, designed and directed the project, and wrote the manuscript. YC and ZC performed electrophysiological recordings and analysis. PR and WS conducted primary cell culturing. WJ, LY and HL conducted mice genotyping. CH, CJ and WR conducted drug delivery. ML helped to perform microdialysis analysis and WF constructed genomic mice strains. WZ, AJ, WY and ZX helped with data interpretation. YZ supervised the project and wrote the paper.

Author information

Author notes

    • M Jun
    •  & Q Xiaolong

    These authors contributed equally to this work.

Affiliations

  1. The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China

    • M Jun
    • , W Shukun
    • , C Jinbo
    • , W Rong
    • , L Yajin
    •  & Y Zengqiang
  2. State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    • M Jun
    • , Q Xiaolong
    • , P Ruiyuan
    • , W Junbing
    • , H Li
    •  & C Hong
  3. Department of Anesthesiology, Pain Medicine & Critical Care Medicine, Aviation General Hospital of China Medical University, Beijing, China

    • M Jun
    •  & A Jianxiong
  4. State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China

    • Y Chaojuan
    •  & Z Chen
  5. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, the Chinese Academy of Sciences, Beijing, China

    • M Lanqun
  6. National Institute of Biological Sciences, Beijing, China

    • W Fengchao
  7. Department of Neurology and Research Center of Neurology in Second Affiliated Hosipital, and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hanzhou, Zhejiang, China

    • W Zhiying
  8. Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, China

    • W Yun
  9. University of Ottawa Institute of Mental Health Research, Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada

    • Z Xia
  10. Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, China

    • Y Zengqiang

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Y Zengqiang.

Supplementary information

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)