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

Zhongke Wang, Ruxin Xie, Xiaolin Yang, Huachun Yin, Xin Li, Tianyao Liu, Yuanyuan Ma, Junwei Gao, Zhenle Zang, Ruotong Ruan, Yang Li, Kaixuan Huang, Qingbo Chen, Kaifeng Shen, Shengqing Lv, Chunqing Zhang, Hui Yang, Maragret Warner, Jan Ake Gustafsson, Shiyong LiuXiaotang Fan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)6074-6089
Number of pages16
JournalTheranostics
Volume11
Issue number12
DOIs
StatePublished - 2021

Keywords

  • ERβ
  • Estrogen
  • Hippocampus
  • Synapse
  • Temporal lobe epilepsy

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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