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Astrocyte-derived ATP modulates depressive-like behaviors

Nature Medicine volume 19, pages 773777 (2013) | Download Citation

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Abstract

Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the world's population1; however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology2,3,4,5,6,7. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a Gq G protein–coupled receptor only in astrocytes to enable selective activation of astrocytic Ca2+ signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD.

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Acknowledgements

We thank J. Chen (University of California, San Diego) for providing Itpr2+/− mice and P.G. Haydon (Tufts University School of Medicine, Boston) for providing GFAP-tTA and tetO.SNARE mouse lines. We thank L. Mei for his insightful suggestions. This work was partly supported by the National Natural Science Foundation of China (grants 81171276, 8103002 and U1201225), the Key Project of Guangdong Province (grants 9351051501000003 and CXZB1018), the Guangzhou Science and Technology Project (grant 7411802013939), the Major State Basic Research Program of China (grant 2012CB518203), the Program for Changjiang Scholars and Innovative Research Team in University (grant IRT1142) and the Project supported by Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2011).

Author information

Affiliations

  1. Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.

    • Xiong Cao
    • , Liang-Ping Li
    • , Qian Wang
    • , Qiong Wu
    • , Hong-Hai Hu
    • , Meng Zhang
    • , Ying-Ying Fang
    • , Jie Zhang
    • , Shu-Ji Li
    • , Wen-Chao Xiong
    • , Hua-Cheng Yan
    • , Yu-Bo Gao
    • , Ji-Hong Liu
    • , Xiao-Wen Li
    • , Li-Rong Sun
    • , Yuan-Ning Zeng
    • , Xin-Hong Zhu
    •  & Tian-Ming Gao
  2. Key Laboratory of Neuroplasticity of Guangdong Higher Education Institutes, Southern Medical University, Guangzhou, China.

    • Xiong Cao
    • , Liang-Ping Li
    • , Qian Wang
    • , Qiong Wu
    • , Hong-Hai Hu
    • , Meng Zhang
    • , Ying-Ying Fang
    • , Jie Zhang
    • , Shu-Ji Li
    • , Wen-Chao Xiong
    • , Hua-Cheng Yan
    • , Yu-Bo Gao
    • , Ji-Hong Liu
    • , Xiao-Wen Li
    • , Li-Rong Sun
    • , Yuan-Ning Zeng
    • , Xin-Hong Zhu
    •  & Tian-Ming Gao
  3. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.

    • Xiong Cao
    •  & Xin-Hong Zhu

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Contributions

X.-H.Z. and T.-M.G. designed the research. X.C., L.-P.L., Q. Wang, J.Z., W.-C.X., Y.-B.G., X.-W.L., Y.-Y.F., Y.-N.Z. and H.-C.Y. conducted the behavioral tests and analysis. X.C., L.-P. L., Q. Wu, M.Z. and J.-H.L. performed the ELISA and ATP measurements. X.C. and L.-R.S. contributed to the HPLC analysis. X.C. performed the immunofluorescence, calcium imaging, osmotic minipump implantation and stereotaxic microinjection. L.-P.L., X.C. and S.-J.L. performed the cell culture. Q. Wu and H.-H.H. performed the western blotting. X.-H.Z., T.-M.G. and X.C. analyzed the data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Xin-Hong Zhu or Tian-Ming Gao.

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DOI

https://doi.org/10.1038/nm.3162

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