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Astroglial kappa opioid receptor-mediated reduction of glutamate exchanger xCT in the prelimbic cortex underlies chronic stress-induced depressive-like behaviors

Molecular Psychiatry (2025)Cite this article

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Abstract

Multiple lines of evidence, including clinical and preclinical, associate depression with dysregulated glutamate homeostasis in the central nervous system. The astrocyte-enriched cysteine/glutamate antiporter, xCT, plays a pivotal role in maintaining this homeostasis, and its dysfunction is linked to depressive-like behaviors induced by chronic stress. However, the exact mechanism through which chronic stress results in xCT dysfunction remains poorly understood. In this study, we demonstrate that chronic social defeat stress (CSDS) downregulates xCT expression in the prelimbic cortex (PL), a key cortical region involved in the aetiology of depression, through astroglial kappa opioid receptor (KOR)-dependent, p38 MAPK-mediated upregulation of miR-3084-5p expression, which in turn downregulates xCT expression by inhibiting mRNA that encodes xCT. Knockdown of KORs as well as overexpression of xCT in the PL astrocytes significantly attenuates CSDS-induced depressive-like behaviors. Blockade of p38 MAPK activity or suppression of miR-3084-5p function restores xCT expression and alleviates depressive-like behaviors. Together, this study reveals a novel mechanism by which chronic stress deregulates glutamate homeostasis and consequently results in depression.

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Fig. 1: CSDS induces depressive-like behaviors by activating dynorphin/KOR signaling in the PL, and inhibition or knockdown of KOR in the PL alleviates depressive-like behaviors.
Fig. 2: KOR-mediated upregulation of p38 MAPK activity and downregulation of xCT expression in the PL contribute to CSDS-induced depressive-like behaviors.
Fig. 3: CSDS enhances miR-3084-5p expression via the KOR/p38 MAPK pathway, potentially targeting the xCT gene in the PL.
Fig. 4: Inhibition of miR-3084-5p or overexpression of xCT in the PL ameliorates depressive-like behaviors induced by CSDS.
Fig. 5: KORs are present in astrocytes and knockdown of astroglial KORs in the PL alleviates CSDS-induced depressive-like behaviors.
Fig. 6: Either knockdown of astroglial miRNA-3084-5p or overexpression of astroglial xCT in the PL reverses CSDS-induced depressive-like behaviors.
Fig. 7: Mechanism diagram of astroglial KOR-mediated xCT reduction in stress-induced depressive-like behaviors.

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Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This research was supported by the Major Project of the Science and Technology Innovation 2030 of China (STI2030-Major Projects 2021ZD0202900 to J.-G.L., 2021ZD0203500 to Y.-J.W.), from the National Natural Science Foundation of China (82030112 to J.-G.L., 82273904 to G.-Y.Z.), from the Key R&D Program of Shandong Province, China (2024CXPT029 to Y.J. W), from the Fundamental Research Projects of Science & Technology Innovation and development Plan in Yantai City (No.2024JCYJ045 to Y.J. W), from Science and Technology Commission of Shanghai Municipality 23ZR1474900 to Y.-J.W.), and from the Taishan Scholars Program and Shandong Laboratory Program (SYS202205).

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  1. These authors contributed equally: Yexiang Chen, Liu-Bin Guo, Gui-Ying Zan.

Authors and Affiliations

  1. Key Laboratory of Acupuncture and Neurobiology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Yexiang Chen, Chi Xu, Boyu Liu, Xiaofen He, Xiaomei Shao, Jianqiao Fang & Jing-Gen Liu

  2. CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Yexiang Chen, Liu-Bin Guo, Gui-Ying Zan, Zihan Liu, Jian-Dong Long, Jing-Gen Liu & Yu-Jun Wang

  3. School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

    Liu-Bin Guo

  4. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Song-Yu Yao

  5. Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Shuo Wu, Xingcong Jiang & Boyu Liu

  6. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China

    Zihan Liu & Yu-Jun Wang

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  5. Song-Yu Yao
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  7. Xingcong Jiang
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  8. Zihan Liu
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  9. Jian-Dong Long
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  10. Boyu Liu
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  11. Xiaofen He
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  12. Xiaomei Shao
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  13. Jianqiao Fang
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  14. Jing-Gen Liu
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  15. Yu-Jun Wang
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Contributions

Yu-Jun Wang, Jing-Gen Liu, Jiaoqiao Fang and Xiaomei Shao designed the experiments. Yexiang Chen, Liu-Bin Guo and Guiying Zan performed the experiments and statistical analysis with the assistance of Chi Xu, Song-Yu Yao, Shuo Wu, Xingcong Jiang, Zihan Liu, Jian-Dong Long, Boyu Liu and Xiaofen He. The manuscript was written by Yexiang Chen, Jing-Gen Liu and Yu-Jun Wang, and was revised by Xiaomei Shao and Jiaoqiao Fang.

Corresponding authors

Correspondence to Xiaomei Shao, Jianqiao Fang, Jing-Gen Liu or Yu-Jun Wang.

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The authors declare no competing interests.

Ethics approval and consent to participate

All animal experiments and procedures were approved by the Animal Care and Use Committee of Shanghai Institute of Materia Medica, Chinese Academy of Sciences (Approval No. 2022-07-LJG-76).Written informed consent was not required, as no human participant was involved in this study. All methods were performed in accordance with the relevant guidelines and regulations.

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Chen, Y., Guo, LB., Zan, GY. et al. Astroglial kappa opioid receptor-mediated reduction of glutamate exchanger xCT in the prelimbic cortex underlies chronic stress-induced depressive-like behaviors. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03441-y

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