E4BP4 Coordinates Circadian Control of Cognition in Delirium

Chen, Min1,2; Zhang, Li2; Shao, Mingting3; Du, Jianhao2; Xiao, Yifei1; Zhang, Fugui1; Zhang, Tianpeng1; Li, Yifang2; Zhou, Qianqian4,5; Liu, Kaisheng4,5; Wang, Zhigang6; Wu, Baojian1

2022-06-01

10.1002/advs.202200559

ADVANCED SCIENCE   Impact Factor & Quartile

2198-3844

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.

circadian rhythm delirium E4BP4 ERK1 2 microglia

SCI

English

Corresponding

National Natural Science Foundation of China[81802749] ; Science and Technology Foundation of Shenzhen City["JCYJ20200109144410181","JCYJ20180301170047864"] ; Natural Science Foundation of Guangdong Province[2020A1515010538]

Chemistry ; Science & Technology - Other Topics ; Materials Science

Chemistry, Multidisciplinary ; Nanoscience & Nanotechnology ; Materials Science, Multidisciplinary

WOS:000812293200001

WILEY

Web of Science

1.Guangzhou Univ Chinese Med, Inst Mol Rhythm & Metab, Guangzhou 510006, Peoples R China
2.Jinan Univ, Coll Pharm, Guangzhou 510632, Peoples R China
3.Jinan Univ, Guangdong Hongkong Macau Inst CNS Regenerat, Guangzhou 510632, Peoples R China
4.Jinan Univ, Shenzhen Peoples Hosp, Clin Med Coll 2, Shenzhen 518119, Peoples R China
5.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518119, Peoples R China
6.Jinan Univ, Affiliated Hosp 1, Dept Intens Care Unit, Guangzhou 510630, Peoples R China

Chen, Min,Zhang, Li,Shao, Mingting,et al. E4BP4 Coordinates Circadian Control of Cognition in Delirium[J]. ADVANCED SCIENCE,2022.

Chen, Min.,Zhang, Li.,Shao, Mingting.,Du, Jianhao.,Xiao, Yifei.,...&Wu, Baojian.(2022).E4BP4 Coordinates Circadian Control of Cognition in Delirium.ADVANCED SCIENCE.

Chen, Min,et al."E4BP4 Coordinates Circadian Control of Cognition in Delirium".ADVANCED SCIENCE (2022).