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Human mood disorder risk gene Synaptotagmin-14 contributes to mania-like behaviors in mice

Molecular Psychiatry volume 30, pages 3466–3477 (2025)Cite this article

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Abstract

Bipolar disorder (BD) and major depressive disorder (MDD) are the most prevalent mood disorders and cause considerable burden worldwide. Compelling evidence suggests a pronounced overlap between these two disorders in clinical symptoms, treatment strategies, and genetic etiology. Here we leverage a BD GWAS (1822 cases and 4650 controls) and a MDD GWAS (5303 cases and 5337 controls), followed by independent replications, to investigate their shared genetic basis among Han Chinese. We have herein identified a lead SNP rs126277 at the 1q32.2 locus, which also exhibited nominal associations with mood disorders and several relevant sub-clinical phenotypes (e.g., mania) in European populations. Bulk tissue and single-cell eQTL analyses suggest that the risk G-allele of rs126277 predicted lower SYT14 mRNA expression in human brains. We generated mice lacking Syt14 (Syt14–/–) and mice with insufficient expression of Syt14 in the hippocampus (Syt14-KD), and found that depletion of Syt14 resulted in mania-like behaviors including hyperactivity and anti-depressive behaviors, resembling aspects of mood disorders. We also confirmed that deficiency of this gene in the hippocampus was sufficient to induce hyperactivity in mice. RNA-sequencing analyses of the hippocampus of Syt14–/– mice revealed significant upregulation of Per1 as well as downregulation of Slc7a11 and Ptprb. Ultrastructural analyses showed significant alteration of the number of vesicles within 50 nm to the active zone and the width of synaptic cleft in the ventral hippocampus of Syt14–/– mice compared with the control mice. Overall, we have identified a novel mood disorder risk gene SYT14, and confirmed its impact on mania-like behaviors. While the current study identifies an essential mood disorder risk gene, further investigations elucidating the detailed mechanisms by which SYT14 contributes to the pathogenesis of the illnesses are needed.

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Fig. 1: Meta-analyses results of Han Chinese BD and MDD GWAS datasets.
Fig. 2: Syt14 deficient mice exhibited mania-like behaviors and impaired motor coordination.
Fig. 3: Reducing Syt14 in the ventral hippocampus of mice exhibited mania-like behaviors.
Fig. 4: Deficiency of Syt14 in the hippocampus alters mRNA expression of genes in RNA-seq analysis.
Fig. 5: Syt14–/– mice exhibit abnormal readily releasable pool of vesicles in the ventral hippocampus.

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Data availability

The data associated with this study could be shared upon reasonable request to the corresponding author.

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Acknowledgements

This study was supported by National Natural Science Foundation of China (82222024 to X.X., 82225016 to M.L., U22A20304 to S.W.L.); Yunnan Fundamental Research Projects (202201AT070120 and 202401AS070084 to X.X., 202201AS070048 and 202401AS070080 to M.L., 202301AW070009 to S.W.L., 202305AH340007); Spring City Plan: the High-level Talent Promotion and Training Project of Kunming (2022SCP001); CAS “Light of West China” Program (xbzg-zdsys-202312). Xiao Xiao was also supported by the CAS “Light of West China” Program, CAS Youth Innovation Promotion Association, and Yunnan Revitalization Talent Support Program Young Talent Project. Shi-Wu Li was also supported by the Yunnan Revitalization Talent Support Program Young Talent Project. Ming Li was also supported by the Yunnan Revitalization Talent Support Program Yunling Scholar Project. PsychENCODE Consortium Data were generated as part of the PsychENCODE Consortium. Visit 10.7303/syn26365932 for a complete list of grants and PIs.

Author information

Author notes

  1. These authors contributed equally: Yue Zhang, Chu-Yi Zhang, Jing Yuan, Hongyan Jiang.

Authors and Affiliations

  1. State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Yue Zhang, Chu-Yi Zhang, Lu Wang, Yi Yang, Ming Li, Shi-Wu Li & Xiao Xiao

  2. Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Yue Zhang, Chu-Yi Zhang, Lu Wang, Yi Yang, Ming Li, Shi-Wu Li & Xiao Xiao

  3. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China

    Yue Zhang, Chu-Yi Zhang, Yi Yang, Ming Li & Xiao Xiao

  4. Department of Psychiatry, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China

    Jing Yuan & Li Xu

  5. Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China

    Hongyan Jiang

  6. Qingdao Mental Health Center, Qingdao, Shandong, China

    Ping Sun

  7. Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, China

    Li Hui

  8. Key Laboratory of Neurological and Psychiatric Disease Research of Yunnan Province, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China

    Ling Yu, Zeyi Guo & Zhaowei Teng

  9. Department of Psychiatry, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Jianzhong Yang

  10. The Key Laboratory of Mental Disorder Management in Zhejiang Province, Hangzhou, Zhejiang, China

    Jianzhong Yang

  11. Department of Blood Transfusion, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China

    Wei Li

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  11. Yi Yang
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  12. Ming Li
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  13. Shi-Wu Li
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  15. Wei Li
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  17. Xiao Xiao
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Contributions

XX conceived and designed the study. YZ conducted the murine experiments with the help of LW, YY, SWL and WL. CYZ performed the statistical analyses. JY, HJ, PS, LH, LX, LY, ZG, JY and ZT contributed sample collection. ML provided advice and extensive discussion during the design and practice of the present study. XX, ML, CYZ and YZ drafted the first version of the manuscript. All authors revised the manuscript critically and approved the final version.

Corresponding author

Correspondence to Xiao Xiao.

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Zhang, Y., Zhang, CY., Yuan, J. et al. Human mood disorder risk gene Synaptotagmin-14 contributes to mania-like behaviors in mice. Mol Psychiatry 30, 3466–3477 (2025). https://doi.org/10.1038/s41380-025-02933-1

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