Article

Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression

  • Nature volume 554, pages 323327 (15 February 2018)
  • doi:10.1038/nature25752
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Abstract

Enhanced bursting activity of neurons in the lateral habenula (LHb) is essential in driving depression-like behaviours, but the cause of this increase has been unknown. Here, using a high-throughput quantitative proteomic screen, we show that an astroglial potassium channel (Kir4.1) is upregulated in the LHb in rat models of depression. Kir4.1 in the LHb shows a distinct pattern of expression on astrocytic membrane processes that wrap tightly around the neuronal soma. Electrophysiology and modelling data show that the level of Kir4.1 on astrocytes tightly regulates the degree of membrane hyperpolarization and the amount of bursting activity of LHb neurons. Astrocyte-specific gain and loss of Kir4.1 in the LHb bidirectionally regulates neuronal bursting and depression-like symptoms. Together, these results show that a glia–neuron interaction at the perisomatic space of LHb is involved in setting the neuronal firing mode in models of a major psychiatric disease. Kir4.1 in the LHb might have potential as a target for treating clinical depression.

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Acknowledgements

We thank K. McCarthy for Kir4.1 floxed mice; B. Khakh for the GFAP-Kir4.1 plasmid; T. Xue for advice on dn-Kir4.1 design; Y.-Y. Liu for technical support on electromicroscopy; C. Liu and C.-J. Shen for help with immunohistochemistry; S.-M. Duan, Y.-D. Zhou, J.-W. Zhao, X.-H. Zhang and B. MacVicar for advice on experimental design; and C. Giaum and P. Magistretti for comments on the manuscript. This work was supported by grants from the National Key R&D Program of China (2016YFA0501000), the National Natural Science Foundation of China (91432108, 31225010, and 81527901 to H.H., 81701335 to Y.C., and 81730035 to S.W.), the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02030004) and 111 project (B13026) to H.H.

Author information

Affiliations

  1. Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Interdisciplinary Institute of Neuroscience and Technology, Qiushi Academy for Advanced Studies, Zhejiang University, Hangzhou 310058, China.

    • Yihui Cui
    • , Yan Yang
    • , Zheyi Ni
    • , Yiyan Dong
    • , Shuangshuang Ma
    • , Kangning Sang
    • , Siyang Tang
    • , Yuezhou Li
    • , Ying Shen
    •  & Hailan Hu
  2. Mental Health Center, School of Medicine, Zhejiang University, Hangzhou 310013, China.

    • Yihui Cui
    • , Yan Yang
    •  & Hailan Hu
  3. Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China.

    • Guohong Cai
    •  & Shengxi Wu
  4. INRIA, Lyon, F-69603, France.

    • Alexandre Foncelle
    •  & Hugues Berry
  5. University of Lyon, UMR 5205, CNRS, LIRIS, F-69622, France.

    • Alexandre Foncelle
    •  & Hugues Berry

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Contributions

Y.C. performed the in vitro patch recordings; Y.Y. performed the biochemistry and immunohistochemistry experiments; Y.C., Y.Y., Y.D. and K.S. performed viral injections and behavioural experiments; Z.N., A.F. and H.B. established the biophysical model; S.M. assisted with cell culture experiments; G.C. and S.W. conducted the electron microscopy experiments; Y.S. contributed Kir4.1 floxed mice; S.T. and Y.L. constructed plasmids; H.H. and Y.C. designed the study; and H.H. wrote the manuscript with the assistance of Y.C., Y.Y. and Z.N.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Hailan Hu.

Reviewer Information Nature thanks P. Kenny and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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    Supplementary Table 2

    This file contains the model parameters and a detailed model description.

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