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NEK4 modulates circadian fluctuations of emotional behaviors and synaptogenesis in male mice

Author

Listed:
  • Zhi-Hui Yang

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xin Cai

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Chu-Yi Zhang

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Qing Zhang

    (Ningbo University
    Ningbo University)

  • Miao Li

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Zhong-Li Ding

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Yingqi Guo

    (Chinese Academy of Sciences)

  • Guolan Ma

    (Chinese Academy of Sciences)

  • Chao-Hao Yang

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Lei Guo

    (Ningbo University
    Ningbo University)

  • Hong Chang

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Chuang Wang

    (Ningbo University
    Ningbo University)

  • Ming Li

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Xiao Xiao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

Abstract

GWASs have linked the 3p21.1 locus, which is associated with the expression levels of NEK4, to bipolar disorder. Here, we use integrative analyses of GWAS statistics and eQTL annotations to establish that elevated NEK4 expression in the hippocampus is associated with an increased risk of bipolar disorder. To further study this association, we generate transgenic male mice that conditionally overexpress NEK4 in the pyramidal neurons of the adult forebrain, or use AAV to overexpress NEK4 in the dorsal hippocampus. Compared to the control mice, male mice of both strains exhibit a shift from a diurnal anxiety state to a nocturnal normal or anxiolytic-like state. Overexpression of NEK4 also affects the circadian fluctuations in dendritic spine morphology and synaptic structure. Furthermore, we show that treatment with lithium ameliorates the effects of NEK4 overexpression in male mice. We then perform phosphoproteomic analyses to demonstrate that the diurnal and nocturnal phosphoproteomic profiles of male control and NEK4 overexpressing mice are different. These results suggest that male mice with different NEK4 expression levels may recapitulate some of the core features observed in patients with bipolar disorder, indicating that interruption of the homeostatic dynamics of synapses may underlie the emotional swings in bipolar disorder.

Suggested Citation

  • Zhi-Hui Yang & Xin Cai & Chu-Yi Zhang & Qing Zhang & Miao Li & Zhong-Li Ding & Yingqi Guo & Guolan Ma & Chao-Hao Yang & Lei Guo & Hong Chang & Chuang Wang & Ming Li & Xiao Xiao, 2024. "NEK4 modulates circadian fluctuations of emotional behaviors and synaptogenesis in male mice," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53585-8
    DOI: 10.1038/s41467-024-53585-8
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    1. Kihoon Han & J. Lloyd Holder Jr & Christian P. Schaaf & Hui Lu & Hongmei Chen & Hyojin Kang & Jianrong Tang & Zhenyu Wu & Shuang Hao & Sau Wai Cheung & Peng Yu & Hao Sun & Amy M. Breman & Ankita Patel, 2013. "SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties," Nature, Nature, vol. 503(7474), pages 72-77, November.
    2. Smyth Gordon K, 2004. "Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 3(1), pages 1-28, February.
    3. Li Ma & Feng Wang & Yangping Li & Jing Wang & Qing Chang & Yuanning Du & Jotham Sadan & Zhen Zhao & Guoping Fan & Bing Yao & Jian-Fu Chen, 2023. "Brain methylome remodeling selectively regulates neuronal activity genes linking to emotional behaviors in mice exposed to maternal immune activation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Yingyao Zhou & Bin Zhou & Lars Pache & Max Chang & Alireza Hadj Khodabakhshi & Olga Tanaseichuk & Christopher Benner & Sumit K. Chanda, 2019. "Metascape provides a biologist-oriented resource for the analysis of systems-level datasets," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
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