Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb

Shuangshuang Ma, Min Chen, Yihao Jiang, Xinkuan Xiang, Shiqi Wang, Zuohang Wu, Shuo Li, Yihui Cui, Junying Wang, Yanqing Zhu, Yan Zhang, Huan Ma, Shumin Duan, Haohong Li, Yan Yang, Christopher J. Lingle and Hailan Hu ()
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Shuangshuang Ma: Zhejiang University School of Medicine
Min Chen: Zhejiang University
Yihao Jiang: Zhejiang University
Xinkuan Xiang: Zhejiang University
Shiqi Wang: Zhejiang University
Zuohang Wu: Zhejiang University
Shuo Li: Zhejiang University
Yihui Cui: Zhejiang University
Junying Wang: Zhejiang University
Yanqing Zhu: Zhejiang University
Yan Zhang: Zhejiang University
Huan Ma: Zhejiang University
Shumin Duan: Zhejiang University
Haohong Li: Zhejiang University
Yan Yang: Zhejiang University
Christopher J. Lingle: Washington University School of Medicine
Hailan Hu: Zhejiang University School of Medicine

Nature, 2023, vol. 622, issue 7984, 802-809

Abstract: Abstract Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2–4. Although the elimination half-life of ketamine is only 13 min in mice5, its antidepressant activities can last for at least 24 h6–9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine–NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine–NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.

Date: 2023
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DOI: 10.1038/s41586-023-06624-1

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