Theranostics 2021; 11(12):6074-6089. doi:10.7150/thno.56331 This issue

Research Paper

Female mice lacking ERβ display excitatory/inhibitory synaptic imbalance to drive the pathogenesis of temporal lobe epilepsy

Zhongke Wang1,2, Ruxin Xie2, Xiaolin Yang1, Huachun Yin1, Xin Li2, Tianyao Liu2, Yuanyuan Ma2, Junwei Gao2, Zhenle Zang2, Ruotong Ruan2, Yang Li1, Kaixuan Huang1, Qingbo Chen1, Kaifeng Shen1, Shengqing Lv1, Chunqing Zhang1, Hui Yang1, Maragret Warner3, Jan-Ake Gustafsson3,4✉, Shiyong Liu1✉, Xiaotang Fan2✉

1. Department of Neurosurgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037 Chongqing, China.
2. Department of Developmental Neuropsychology, School of Psychology, Army Medical University (Third Military Medical University), 400038 Chongqing, China.
3. Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77054;
4. Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institute, 141 86 Novum, Sweden.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Wang Z, Xie R, Yang X, Yin H, Li X, Liu T, Ma Y, Gao J, Zang Z, Ruan R, Li Y, Huang K, Chen Q, Shen K, Lv S, Zhang C, Yang H, Warner M, Gustafsson JA, Liu S, Fan X. Female mice lacking ERβ display excitatory/inhibitory synaptic imbalance to drive the pathogenesis of temporal lobe epilepsy. Theranostics 2021; 11(12):6074-6089. doi:10.7150/thno.56331. Available from https://www.thno.org/v11p6074.htm

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Abstract

Graphic abstract

Epilepsy is a highly prevalent and drug-refractory neurological disorder characterized by spontaneous recurrent seizures. Estrogen is identified to be proconvulsant and lowers the seizure threshold of female epilepsy. Estrogen receptor β (ERβ) has been proposed to mediate neuroprotection in epilepsy, although the underlying mechanism remains unknown.

Rationale: In this study, we investigated the role of ERβ in the epileptogenesis of female temporal lobe epilepsy (TLE).

Methods: Immunohistochemistry, immunofluorescence, western blots, Golgi staining, 1H MRS and whole-cell patch-clamp were used to evaluate ERβ expression, pathological changes, and synaptic excitation /inhibition (E/I) balance in female TLE patients and ovariectomized (OVX) chronic epileptic mice. Electroencephalogram (EEG) recordings were recorded to evaluate the epileptic susceptibility in OVX WT and ERβ-/- mice. And high-throughput RNA-sequence was performed to identify differential expression genes (DEGs) which can elucidate the potential mechanism of ERβ regulating the seizure susceptibility.

Results: ERβ expression was decreased in the brains of female TLE patients and OVX chronic epileptic mice. ERβ deletion enhanced seizure susceptibility and exacerbated the imbalance of synaptic E/I in hippocampal CA1 area of OVX epileptic mice. In line with these observations, RNA-sequence data further identified glutamine ligase (GLUL) as the target of ERβ involved in regulating synaptic E/I in CA1. Furthermore, ERβ agonist WAY-200070 markedly suppressed epileptic phenotypes and normalized GLUL expression in CA1 region of kainic acid (KA) induced OVX chronic epileptic model.

Conclusions: Our data provide novel insight into the pathogenesis of female TLE, and indicate ERβ provides a new therapeutic strategy for female TLE patients.

Keywords: ERβ, temporal lobe epilepsy, estrogen, hippocampus, synapse