Nek4 Modulates Circadian Fluctuations Of Emotional Behaviors And Synaptogenesis In Male Mice Zhihui Yang Xin Cai Chuyi Zhang Qing Zhang Miao Li Zhongli Ding Yingqi Guo Guolan Ma Chaohao Yang Lei Guo Hong Chang Chuang Wang Ming Li Xiao Xiao by 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 instant download after payment.

GWASs have linked the 3p21.1 locus, which is associated with the expressionlevels of NEK4, to bipolar disorder. Here, we use integrative analyses ofGWAS statistics and eQTL annotations to establish that elevated NEK4expression in the hippocampus is associated with an increased risk ofbipolar disorder. To further study this association, we generate transgenicmale mice that conditionally overexpress NEK4 in the pyramidal neurons ofthe adult forebrain, or use AAV to overexpress NEK4 in the dorsal hippocampus. Compared to the control mice, male mice of both strains exhibit ashift from a diurnal anxiety state to a nocturnal normal or anxiolytic-likestate. Overexpression of NEK4 also affects the circadian fluctuations indendritic spine morphology and synaptic structure. Furthermore, we showthat treatment with lithium ameliorates the effects of NEK4 overexpressionin male mice. We then perform phosphoproteomic analyses to demonstratethat the diurnal and nocturnal phosphoproteomic profiles of male controland NEK4 overexpressing mice are different. These results suggest that malemice with different NEK4 expression levels may recapitulate some of thecore features observed in patients with bipolar disorder, indicating thatinterruption of the homeostatic dynamics of synapses may underlie theemotional swings in bipolar disorder.