2. Academic Validation
  3. Adenosine signalling drives antidepressant actions of ketamine and ECT

Adenosine signalling drives antidepressant actions of ketamine and ECT

  • Nature. 2025 Nov 5. doi: 10.1038/s41586-025-09755-9.
Chenyu Yue # 1 2 3 4 5,  Na Wang # 2 6,  Haojiang Zhai 7 8,  Zhengwei Yuan 1 2 4,  Yuting Cui 1 2 4,  Jing Quan 1 2 4,  Yu Zhou 1 2 4,  Xiaofeng Fan 2,  Hongshuang Wang 7,  Zhaofa Wu 9,  Huijie Mi 1 2,  Wooping Ge 1 2,  Yulong Li 10 11,  Xiaohui Wang 12 13,  Minmin Luo 14 15 16 17 18
Affiliations

Affiliations

  • 1 Beijing Institute for Brain Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2 Chinese Institute for Brain Research, Beijing, China.
  • 3 National Institute of Biological Sciences, Beijing, China.
  • 4 Research Unit of Medical Neurobiology, Chinese Academy of Medical Sciences, Beijing, China.
  • 5 Peking University-Tsinghua University-NIBS Joint Graduate Program, NIBS, Beijing, China.
  • 6 School of Basic Medical Sciences, Capital Medical University, Beijing, China.
  • 7 Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
  • 8 Department of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, China.
  • 9 Laboratory of Integrative Physiology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 10 State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China.
  • 11 New Cornerstone Science Laboratory, Shenzhen, China.
  • 12 Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China. [email protected].
  • 13 Department of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, China. [email protected].
  • 14 Beijing Institute for Brain Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 15 Chinese Institute for Brain Research, Beijing, China. [email protected].
  • 16 National Institute of Biological Sciences, Beijing, China. [email protected].
  • 17 Research Unit of Medical Neurobiology, Chinese Academy of Medical Sciences, Beijing, China. [email protected].
  • 18 New Cornerstone Science Laboratory, Shenzhen, China. [email protected].
  • # Contributed equally.
PMID: 41193806 DOI: 10.1038/s41586-025-09755-9
Abstract

Ketamine and electroconvulsive therapy (ECT) achieve rapid remission in treatment-resistant depression. However, their mechanisms of action-the understanding of which is essential for refining therapeutic precision-remain unclear1-3. Here, using mouse models, we identify adenosine signalling as a central pathway that underlies the antidepressant effects of these interventions. Results from genetically encoded adenosine sensor experiments and real-time optical recordings reveal that both therapies induce strong adenosine surges in key mood-regulatory regions, including the medial prefrontal cortex and the hippocampus. Genetic or pharmacological disruption of A1 and A2A adenosine receptors abolishes their therapeutic effects, which establishes the essential role of adenosine signalling in antidepressant efficacy. Notably, adenosine signalling specifically in the medial prefrontal cortex drives antidepressant actions. Ketamine increases adenosine by modulating cellular metabolism to increase intracellular adenosine levels without causing neuronal hyperactivity. Leveraging this mechanism, we develop ketamine derivatives that enhance adenosine signalling and exhibit improved antidepressant efficacy with reduced side effects at therapeutic doses. Furthermore, acute intermittent hypoxia, a non-pharmacological intervention involving controlled reductions in oxygen levels, increases brain adenosine levels and produces antidepressant effects, paralleling the actions of ketamine and ECT. Our findings establish adenosine as a pivotal mediator of rapid-acting antidepressants and a tractable target for scalable, noninvasive therapeutics in major depressive disorder.

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