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Selective magnetic stimulation downregulates the GABAA receptor ε subunit in the left prelimbic cortex to alleviate schizophrenia-like behaviors in mice

Molecular Psychiatry volume 31, pages 383–395 (2026)Cite this article

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Abstract

Schizophrenia (SCZ) is a prevalent and disabling mental disorder. Clinically, its complex symptoms, including negative symptoms and cognitive impairment, can be alleviated using electromagnetic techniques such as repetitive transcranial magnetic stimulation (rTMS). To investigate the neural mechanisms of magnetic stimulation and identify selective therapeutic targets, we employed combined magnetic stimulation system treatment (c-MSST). Targeting the left prelimbic cortex (PrL) of mice with c-MSST reversed the SCZ-like behaviors and synaptic abnormalities induced by MK-801 injection and normalized the regional increase in gamma-aminobutyric acid type A receptor subunit epsilon (GABRE) expression. Specific Gabre knockdown in the left PrL ameliorated MK-801-induced SCZ-like behaviors. Importantly, Gabre conditional knock-in mice exhibited SCZ-like behaviors and synaptic plasticity deficits, both of which were reversed by c-MSST. We further demonstrated that the ability of c-MSST to reduce GABRE protein expression may be related to p62/SQSTM1-mediated sequestration of GABARAP family. Our study improves the understanding of the therapeutic mechanisms of magnetic techniques and suggests that Gabre and related molecular circuits are promising targets for SCZ treatment.

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Fig. 1: c-MSST targeting the left PrL ameliorates MK-801-induced SCZ-like behaviors in mice.
Fig. 2: Effect of c-MSST on synaptic plasticity in the left PrL.
Fig. 3: Analysis of bulk RNA-seq data revealed abnormal expression of Gabre.
Fig. 4: Selective downregulation of Gabre in neurons inhibits the SCZ-inducing effects of MK-801.
Fig. 5: c-MSST inhibits SCZ-like behaviors of Gabre CKI mice.
Fig. 6: c-MSST modulates Gabre-mediated synaptic plasticity changes.
Fig. 7: Mechanism underlying the membrane surface expression of GABRE in the left PrL of c-MSST-treated mice.
Fig. 8

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Data availability

The data discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE286434 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE286434).

Code availability

The code required to reanalyze the data reported in this paper can be obtained by contacting the corresponding author.

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Acknowledgements

We thank Prof. Gavin P. Reynolds and Prof. Yan Kong for conceptual discussions and manuscript editing. This work was supported by the National Natural Science Foundation of China (82371510, 82401761, and 82101572), Social Development Foundation of Jiangsu Province, China (No. BE2023668), and Nanjing Major Science and Technology Project (Life and Health, No. 202305035).

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Author notes

  1. These authors contributed equally: Yunshan Hu, Zixu Wang, Jin Fang, Shaotong Zhang.

Authors and Affiliations

  1. Department of Geriatric Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China

    Yunshan Hu, Zixu Wang, Jin Fang, Shaotong Zhang, Yan Li, Chaoran Wu, Yu Wang, Yuru Ling, Renliang Cai, Yue Xu, Xinyu Fang, Chao Zhou & Xiangrong Zhang

  2. Department of Neurology, Affiliated Zhongda Hospital, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease Ministry of Education, Southeast University, Nanjing, Jiangsu, 210096, China

    Dandan Xu, Mengyu Liu & Zhijun Zhang

Authors
  1. Yunshan Hu
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  2. Zixu Wang
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  3. Jin Fang
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  4. Shaotong Zhang
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  5. Yan Li
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  6. Chaoran Wu
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  7. Yu Wang
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  8. Yuru Ling
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  9. Renliang Cai
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  10. Yue Xu
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  11. Xinyu Fang
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  12. Chao Zhou
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  13. Dandan Xu
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  14. Mengyu Liu
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  15. Zhijun Zhang
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  16. Xiangrong Zhang
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Contributions

Conceptualization: XRZ, ZJZ. Experimental design: XRZ, ZJZ, YSH, ZXW. Data analysis: YSH, ZXW, JF, STZ. Investigation: ZXW, YSH, YW, YRL. Visualization: YSH, ZXW, DDX, MYL. Supervision: XRZ, ZJZ. Writing–original draft: YSH, XRZ, ZJZ. Writing–review & editing: all authors.

Corresponding authors

Correspondence to Zhijun Zhang or Xiangrong Zhang.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All experimental procedures involving animals were approved by the Institutional Animal Care and Use Committee of Southeast University (approval number: 20210426008) and were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. No human participants were involved in this study.

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Hu, Y., Wang, Z., Fang, J. et al. Selective magnetic stimulation downregulates the GABAA receptor ε subunit in the left prelimbic cortex to alleviate schizophrenia-like behaviors in mice. Mol Psychiatry 31, 383–395 (2026). https://doi.org/10.1038/s41380-025-03267-8

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