Article | Published:

Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

Nature volume 554, pages 317322 (15 February 2018) | Download Citation

Abstract

The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the ‘anti-reward center’, the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.

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Acknowledgements

We thank L.-S. Yu and J. Pan for performing LC–MS/MS; S.-M. Duan, X.-H. Zhang, X.-W. Chen, Y.-S. Shu, X. Ju, C. Lohmann and W. Yang for advice on experimental design and comments on the manuscript; and N. Lin, L. Zhang and K.-F. Liu for consultation on in vivo recording. 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. and (81600954) to Y.Y., and the 111 project (B13026) to H. H.

Author information

Author notes

    • Yan Yang
    • , Yihui Cui
    • , Kangning Sang
    •  & Yiyan Dong

    These authors contributed equally to this work.

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.

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

    • Yan Yang
    • , Yihui Cui
    • , Kangning Sang
    •  & Hailan Hu

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Contributions

H.H, Y.C and Y.Y. designed the study. Y.C. performed the in vitro patch-clamp experiments. Y.Y. and S.M. conducted the behavioural pharmacology experiments. K.S. performed the in vivo recordings. Y.D. and K.S. performed the optogenetic behaviour experiments. Z.N. established the biophysical model. H.H. conceived the project and wrote the manuscript with the assistance of Y.C., Y. Y. and Z.N.

Competing interests

H.H., Y.Y. and Y.C. are inventors on two patent applications (201710322647.X and 201710322646.5) filed on the basis on this work. The remaining authors declare that they have no competing interests.

Corresponding author

Correspondence to Hailan Hu.

Reviewer Information Nature thanks P. Kenny, H.-S. Shin 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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https://doi.org/10.1038/nature25509

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