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.
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Jun, M., Xiaolong, Q., Chaojuan, Y. et al. Calhm2 governs astrocytic ATP releasing in the development of depression-like behaviors. Mol Psychiatry 23, 883–891 (2018). https://doi.org/10.1038/mp.2017.229
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DOI: https://doi.org/10.1038/mp.2017.229
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