Effects of esketamine on electrophysiology and metabolic reprogramming in brain organoids: insights into antidepressant mechanisms

Mengjie Li^#^{1

2}, Wen Duan^#³, Xiaoyan Hao^{1

2}, Shuangjie Li^{1

2}, Chen Wang^{1

2}, Yuanyuan Liang^{1

2}, Zhengwei Hu¹, Dongrui Ma^{1

2}, Mengnan Guo^{1

2}, Chunyan Zuo^{1

2}, Zhiyun Wang^{1

2}, Yanmei Feng^{1

2}, Chenwei Hao^{1

2}, Shasha Qi^{1

2}, Yuemeng Sun^{1

2}, Mibo Tang¹, Chengyuan Mao¹, Kenji Hashimoto⁴, Yuming Xu^{1

5

6

7}, Junliang Yuan⁸, Jianjun Yang⁹, Changhe Shi^{10

11

12

13

14}

Affiliations

¹ Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.
² Zhengzhou University, Zhengzhou, 450000, Henan, China.
³ Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.
⁴ Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
⁵ NHC Key Laboratory of Prevention and treatment of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.
⁶ Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450000, Henan, China.
⁷ Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.
⁸ Department of Neurology, Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, 100191, Beijing, China. junliangyuan@bjmu.edu.cn.
⁹ Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. yjyangjj@zzu.edu.cn.
¹⁰ Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. shichanghe@zzu.edu.cn.
¹¹ Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450000, Henan, China. shichanghe@zzu.edu.cn.
¹² Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. shichanghe@zzu.edu.cn.
¹³ Department of Neurology, Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, 100191, Beijing, China. shichanghe@zzu.edu.cn.
¹⁴ Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan, China. shichanghe@zzu.edu.cn.

^# Contributed equally.

PMID: 40885845
DOI: 10.1038/s41380-025-03198-4

Effects of esketamine on electrophysiology and metabolic reprogramming in brain organoids: insights into antidepressant mechanisms

Mengjie Li et al. Mol Psychiatry. 2025 Dec.

. 2025 Dec;30(12):6107-6118.

doi: 10.1038/s41380-025-03198-4. Epub 2025 Aug 30.

Authors

Affiliations

¹ Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.
² Zhengzhou University, Zhengzhou, 450000, Henan, China.
³ Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.
⁴ Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
⁵ NHC Key Laboratory of Prevention and treatment of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.
⁶ Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450000, Henan, China.
⁷ Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.
⁸ Department of Neurology, Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, 100191, Beijing, China. junliangyuan@bjmu.edu.cn.
⁹ Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. yjyangjj@zzu.edu.cn.
¹⁰ Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. shichanghe@zzu.edu.cn.
¹¹ Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450000, Henan, China. shichanghe@zzu.edu.cn.
¹² Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. shichanghe@zzu.edu.cn.
¹³ Department of Neurology, Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, 100191, Beijing, China. shichanghe@zzu.edu.cn.
¹⁴ Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan, China. shichanghe@zzu.edu.cn.

^# Contributed equally.

PMID: 40885845
DOI: 10.1038/s41380-025-03198-4

Abstract

Esketamine, commonly used to treat treatment-resistant depression, has pharmacological mechanisms that remain incompletely understood. Brain organoids offer a human-relevant platform for investigating the cellular and molecular effects of drugs. In this study, we investigated the effects of esketamine on the electrophysiology and metabolism of brain organoids derived from iPSCs of healthy control subjects and depressed patients. Continuous monitoring revealed that esketamine treatment significantly decreased both the frequency and amplitude of action potentials, with the most pronounced reduction occurring within 4 h. High concentrations (1.5 mg/L) produced a stronger inhibitory effect, while organoids treated with a low concentration (0.25 mg/L) showed a recovery in action potential frequency after one week, although levels remained below pre-treatment values-a recovery not observed in the high-concentration group. Single-cell RNA sequencing demonstrated that esketamine modulated energy metabolism and induced metabolic reprogramming in a concentration- and time-dependent manner. Furthermore, by inhibiting oxidative phosphorylation and glycolysis separately and assessing cytosolic Ca²⁺ levels, we found that esketamine may regulate NMDAR activity and electrophysiology through energy metabolism pathways. These findings reveal a potential mechanism for esketamine's effects and offer new insights for clinical treatment strategies.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All participants gave written informed consent, and all study procedures were approved by the ethics committee of the First Affiliated Hospital of Zhengzhou University (2013-KY-52; 2022-KY-1358). All methods were performed in accordance with the relevant guidelines and regulations.

References

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Effects of esketamine on electrophysiology and metabolic reprogramming in brain organoids: insights into antidepressant mechanisms

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Effects of esketamine on electrophysiology and metabolic reprogramming in brain organoids: insights into antidepressant mechanisms

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