E4BP4 协调谵妄认知的昼夜节律控制,Advanced Science

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E4BP4 协调谵妄认知的昼夜节律控制
Advanced Science ( IF 14.3 ) Pub Date : 2022-06-17 , DOI: 10.1002/advs.202200559
Min Chen _{1,

2} , Li Zhang ₂ , Mingting Shao ₃ , Jianhao Du ₂ , Yifei Xiao ₁ , Fugui Zhang ₁ , Tianpeng Zhang ₁ , Yifang Li ₂ , Qianqian Zhou ₄ , Kaisheng Liu ₄ , Zhigang Wang ₅ , Baojian Wu ₁

Affiliation

进一步了解谵妄是一种常见且严重的神经精神综合征的病因，将有助于疾病的预防和治疗。在这里，作者研究了昼夜节律在谵妄发病机制中的作用。他们观察到谵妄小鼠模型中昼夜节律的扰动和谵妄患者的时钟基因表达中断。反过来，生理和遗传昼夜节律紊乱会使小鼠对谵妄敏感，并伴有严重的认知障碍。同样，E4bp4的全局删除（E4 启动子结合蛋白）是一种在谵妄情况下显着改变的时钟基因，导致谵妄相关的认知衰退加剧。谵妄模型的认知衰退归因于小胶质细胞的激活和海马体中的长期增强作用受损。单细胞 RNA 测序显示小胶质细胞是E4bp4的调节靶点。E4bp4通过抑制 ERK1/2 信号通路来抑制小胶质细胞的活化。支持这一点的是，缺乏小胶质细胞E4bp4的小鼠容易出现精神错乱，而在海马 CA1 神经元中特异性缺失的E4bp4的小鼠具有正常的表型。机制上，E4bp4通过反式抑制Mapk1/3抑制 ERK1/2 信号传导（编码 ERK1/2 的基因）通过直接结合启动子区域中的 D-box 元件。这些发现定义了时钟功能障碍在谵妄发展中的因果作用，并表明E4bp4在生物钟和谵妄之间的串扰中是认知调节器。

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E4BP4 Coordinates Circadian Control of Cognition in Delirium

Improved understanding of the etiologies of delirium, a common and severe neuropsychiatric syndrome, would facilitate the disease prevention and treatment. Here, the authors invesitgate the role of circadian rhythms in the pathogenesis of delirium. They observe perturbance of circadian rhythms in mouse models of delirium and disrupted clock gene expression in patients with delirium. In turn, physiological and genetic circadian disruptions sensitize mice to delirium with aggravated cognitive impairment. Likewise, global deletion of E4bp4 (E4 promoter-binding protein), a clock gene markedly altered in delirium conditions, results in exacerbated delirium-associated cognitive decline. Cognitive decline in delirium models is attributed to microglial activation and impaired long-term potentiation in the hippocampus. Single-cell RNA-sequencing reveals microglia as the regulatory target of E4bp4. E4bp4 restrains microglial activation via inhibiting the ERK1/2 signaling pathway. Supporting this, mice lacking in microglial E4bp4 are delirious prone, whereas mice with E4bp4 specifically deleted in hippocampal CA1 neurons have a normal phenotype. Mechanistically, E4bp4 inhibits ERK1/2 signaling by trans-repressing Mapk1/3 (genes encoding ERK1/2) via direct binding to a D-box element in the promoter region. These findings define a causal role of clock dysfunction in delirium development and indicate E4bp4 as a regulator of cognition at the crosstalk between circadian clock and delirium.

更新日期：2022-06-17

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