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Cannabidiol ameliorates cognitive decline in 5×FAD mouse model of Alzheimer’s disease through potentiating the function of extrasynaptic glycine receptors

Molecular Psychiatry volume 30, pages 1817–1827 (2025)Cite this article

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Abstract

Emerging evidence supports the therapeutic potential of cannabinoids in Alzheimer’s disease (AD), but the underlying mechanism upon how cannabinoids impact brain cognition and AD pathology remains unclear. Here we show that chronic cannabidiol (CBD) administration significantly mitigates cognitive deficiency and hippocampal β-amyloid (Aβ) pathology in 5×FAD mouse model of AD. CBD achieves its curative effect mainly through potentiating the function of inhibitory extrasynaptic glycine receptor (GlyR) in hippocampal dentate gyrus (DG). Based on the in vitro and in vivo electrophysiological recording and calcium imaging, CBD mediated anti-AD effects via GlyR are mainly accomplished by decreasing neuronal hyperactivity of granule cells in the DG of AD mice. Furthermore, the AAV-mediated ablation of DG GlyRα1, or the GlyRα1S296A mutation that exclusively disrupts CBD binding, significantly intercepts the anti-AD effect of CBD. These findings suggest a GlyR dependent mechanism underlying the therapeutic potential of CBD in the treatment of AD.

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Fig. 1: Effects of chronic CBD administration on cognitive function in AD.
Fig. 2: Effects of chronic CBD administration on Aβ pathology in AD.
Fig. 3: Characteristics of GlyR in CBD mediated anti-AD effects.
Fig. 4: Effects of GlyRɑ1 S296A mutation on CBD mediated anti-AD effects.
Fig. 5: Effects of chronic CBD administration on DG neuronal excitability of 5× FAD mice.
Fig. 6: Effects of acute CBD infusion into DG on neural hyperactivity of 5× FAD mice.

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Data availability

Further information and requests for data and reagents should be directed to and will be fulfilled by the corresponding author upon request, Guichang Zou (guicz@sdfmu.edu.cn).

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Acknowledgements

We thank Dr. Tao Pan for the synthesis of CBD. This work was supported by National Key R&D Program of China (2021YFA0804900, 2020YFA0112203), National Natural Science Foundation of China (Grants 32225020, 32430045, 91849206, 91942315, 92049304, 32121002 to WX; 82471444, 81901157 and 82241032 to GZ), the Academic Promotion Program of Shandong First Medical University (Grants 2023ZL001), the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant XDB39050000), Key Research Program of Frontier Science (CAS, Grant No. ZDBS-LY-SM002), CAS Interdisciplinary Innovation Team (JCTD-2018-20), the Youth Innovation Promotion Association CAS, the Fundamental Research Funds for the Central Universities, USTC Research Funds of the Double First-Class Initiative (YD9100002001), CAS Project for Young Scientists in Basic Research (YSBR-013), CAS Collaborative Innovation Program of Hefei Science Center (2021HSC-CIP003), Taishan Scholars Program of Shandong Province (tsqn202312236), the Shandong University Youth Innovation Team Development Plan (2023KJ180), the Shandong Postdoctoral Science Foundation (SDBX202302023, SDCX-ZG-202400157), Postdoctoral Fellowship Program of CPSF under Grant Number BX20240355, Joint Innovation Team for Clinical & Basic Research (202404), Excellent Youth Fund Project supported by Shandong Provincial National Science Foundation (ZR2024YQ040), and Research Funds of Center for Advanced Interdisciplinary Science and Biomedicine of IHM (QYZD20230011).

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  1. These authors contributed equally: Jin Jin, Chonglei Fu, Jing Xia, Heyi Luo.

Authors and Affiliations

  1. Department of neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China

    Jin Jin, Jing Xia, Heyi Luo, Xianglian Wang, Huanhuan Mao & Wei Xiong

  2. Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, China

    Chonglei Fu, Si Chen, Lin Lu & Guichang Zou

  3. Shandong Institute of Brain Science and Brain-inspired Research, Jinan, 250117, China

    Chonglei Fu, Lin Lu & Guichang Zou

  4. 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), Chinese Academy of Medical Sciences Research Unit (No.2018RU006), Peking University, 100191, Beijing, China

    Kai Yuan & Lin Lu

  5. Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, 230088, China

    Wei Xiong

  6. CAS Key Laboratory of Brain Function and Disease, Hefei, 230026, China

    Wei Xiong

  7. Anhui Province Key Laboratory of Biomedical Aging Research, Hefei, 230026, China

    Wei Xiong

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Contributions

GZ and WX initiated, designed and supervised the project; GZ, JJ and HL conducted electrophysiological recordings; JX, JJ and SC conducted behavior tests; JJ and CF conducted immunohistochemistry; HL, HM, KY, XW and CF conducted the in vivo recording experiments. GZ, WX and LL wrote the manuscript.

Corresponding authors

Correspondence to Lin Lu, Wei Xiong or Guichang Zou.

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The authors declare no competing interests.

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All methods in this study were performed in accordance with relevant guidelines and regulations. Ethical approval was obtained from the Institutional Review Board of Shandong First Medical University, with reference number W202406120618. Informed consent was obtained from all participants involved in the study.

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Jin, J., Fu, C., Xia, J. et al. Cannabidiol ameliorates cognitive decline in 5×FAD mouse model of Alzheimer’s disease through potentiating the function of extrasynaptic glycine receptors. Mol Psychiatry 30, 1817–1827 (2025). https://doi.org/10.1038/s41380-024-02789-x

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