Differential Effects of ERα and ERβ on Epileptiform Activity in Cultured Hippocampal Neurons

Estrogen exerts broad regulatory effects on numerous physiological processes. The synthesis, fluctuation, and central nervous system signaling of this key neurosteroid are particularly relevant to understanding the heightened vulnerability to seizures observed in women, a relationship that continues to be a major focus of investigation [1]. However, the precise mechanisms underlying estrogen’s complex, dose-dependent effects in epilepsy, particularly those mediated by specific nuclear receptors, remain incompletely understood, thereby complicating the treatment of catamenial epilepsy. Herein, in vitro model experiments indicated that the suppressive effects of 17-β-estradiol (the primary form of estrogen) on epileptiform burst activity in pyramidal hippocampal neurons exhibited a dose-related U-shaped curve, and the most effective concentration was 0.1 ng/mL. Moreover, ERβ was found to mediate the suppressive effects of physiological estrogen levels on epileptiform bursts, whereas ERα exerted opposing, pro-excitatory effects. The roles of estrogen receptors in catamenial epilepsy identified herein might explain the paradoxical U-shaped response and complex estrogen-mediated mechanisms.