Dysregulation of REV-ERBα impairs GABAergic function and promotes epileptic seizures in preclinical models

Tianpeng Zhang, Fangjun Yu, Haiman Xu, Min Chen, Xun Chen, Lianxia Guo, Cui Zhou, Yuting Xu, Fei Wang, Jiandong Yu () and Baojian Wu ()
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Tianpeng Zhang: Guangzhou University of Chinese Medicine
Fangjun Yu: College of Pharmacy, Jinan University
Haiman Xu: College of Pharmacy, Jinan University
Min Chen: College of Pharmacy, Jinan University
Xun Chen: College of Pharmacy, Jinan University
Lianxia Guo: College of Pharmacy, Jinan University
Cui Zhou: College of Pharmacy, Jinan University
Yuting Xu: Southern Medical University
Fei Wang: College of Pharmacy, Jinan University
Jiandong Yu: Jinan University
Baojian Wu: Guangzhou University of Chinese Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract To design potentially more effective therapies, we need to further understand the mechanisms underlying epilepsy. Here, we uncover the role of Rev-erbα in circadian regulation of epileptic seizures. We first show up-regulation of REV-ERBα/Rev-erbα in brain tissues from patients with epilepsy and a mouse model. Ablation or pharmacological modulation of Rev-erbα in mice decreases the susceptibility to acute and chronic seizures, and abolishes diurnal rhythmicity in seizure severity, whereas activation of Rev-erbα increases the animal susceptibility. Rev-erbα ablation or antagonism also leads to prolonged spontaneous inhibitory postsynaptic currents and elevated frequency in the mouse hippocampus, indicating enhanced GABAergic signaling. We also identify the transporters Slc6a1 and Slc6a11 as regulators of Rev-erbα-mediated clearance of GABA. Mechanistically, Rev-erbα promotes the expressions of Slc6a1 and Slc6a11 through transcriptional repression of E4bp4. Our findings propose Rev-erbα as a regulator of synaptic function at the crosstalk between pathways regulating the circadian clock and epilepsy.

Date: 2021
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DOI: 10.1038/s41467-021-21477-w

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