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

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 beta (ER beta) has been proposed to mediate neuroprotection in epilepsy, although the underlying mechanism remains unknown. Rationale: In this study, we investigated the role of ER beta in the epileptogenesis of female temporal lobe epilepsy (TLE). Methods: Immunohistochemistry, immunofluorescence, western blots, Golgi staining, H-1 MRS and whole-cell patch-clamp were used to evaluate ER beta 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 ER beta(-/-) mice. And high-throughput RNA-sequence was performed to identify differential expression genes (DEGs) which can elucidate the potential mechanism of ER beta regulating the seizure susceptibility. Results: ER beta expression was decreased in the brains of female TLE patients and OVX chronic epileptic mice. ER beta 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 ER beta involved in regulating synaptic E/I in CA1. Furthermore, ER beta 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 ER beta provides a new therapeutic strategy for female TLE patients.

Automated summary

The study found that the expression of estrogen receptor beta is decreased in female temporal lobe epilepsy, and its deletion exacerbates seizure susceptibility and imbalance in synaptic excitation/inhibition. ER beta may regulate synaptic E/I through the GLUL gene, providing a potential therapeutic target for female temporal lobe epilepsy patients.