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

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 () and Xiao Xiao ()
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Zhi-Hui Yang: Chinese Academy of Sciences
Xin Cai: Chinese Academy of Sciences
Chu-Yi Zhang: Chinese Academy of Sciences
Qing Zhang: Ningbo University
Miao Li: Chinese Academy of Sciences
Zhong-Li Ding: Chinese Academy of Sciences
Yingqi Guo: Chinese Academy of Sciences
Guolan Ma: Chinese Academy of Sciences
Chao-Hao Yang: Chinese Academy of Sciences
Lei Guo: Ningbo University
Hong Chang: Chinese Academy of Sciences
Chuang Wang: Ningbo University
Ming Li: Chinese Academy of Sciences
Xiao Xiao: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53585-8

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