Estrogen suppresses epileptiform activity by enhancing Kv4.2-mediated transient outward potassium currents in primary hippocampal neurons

Abstract

Catamenial epilepsy is a common phenomenon in female epileptic patients that is, in part, influenced by the 17-β-estradiol level during the menstrual cycle, which modulates the strength of the epileptic seizures. However, the underlying mechanism(s) for catamenial epilepsy remains unknown. In the present study, the effect of 17‑β‑estradiol on modulating epileptiform activities was investigated in cultured hippocampal neurons by focusing on the transient outward potassium current. Using the patch clamp technique, 17‑β‑estradiol was demonstrated to have a dose‑dependent U‑shape effect on epileptiform bursting activities in cultured hippocampal neurons; only the low dose (~0.1 ng/ml) of 17‑β‑estradiol had a suppressive effect on the epileptiform activities. The blockade effect of the low dose 17‑β‑estradiol could be suppressed by phrixotoxin2 (PaTx2), a selective channel blocker for voltage‑gated potassium channel type 4.2 (Kv4.2), which mediates the transient outward potassium current. Furthermore, the 17‑β‑estradiol bell‑shape‑like dose‑dependently enhanced the transient outward potassium current, which was inhibited by the estrogen receptor antagonist ICI 182,780. In conclusion, these results indicate that reduced activation of the transient outward potassium current by a high (or none) 17‑β‑estradiol level may enhance the epileptiform bursting activities in neurons, which may be one of the triggering causes for catamenial epilepsy, and therefore, maintaining a certain low 17‑β‑estradiol level may aid in the control of catamenial epilepsy.

Effects of the estrous cycle and ovarian hormones on cue-triggered motivation and intrinsic excitability of medium spiny neurons in the Nucleus Accumbens core of female rats

“…The reduction in excitability during proestrus/estrus vs. metestrus/diestrus within obesity-prone rats is consistent with the ability of estradiol to enhance I A , thereby reducing excitability in cultured hippocampal neurons ( Zhang et al, 2015 ). Progesterone also increases during the proestrus phase, and relatively high concentrations of exogenous progesterone can result in decreased neuronal excitability in part through altering the activity of voltage-gated sodium and calcium channels ( Kelley and Mermelstein, 2011 ).…”

KCC2 downregulation facilitates epileptic seizures

“…Embryos were prepared from day 18 embryonic Sprague Dawley (SD) rats under ether anesthesia similar to our reported work 41–43 . Briefly, hippocampus was dissected out and digested in 0.05% trypsin-EDTA solution for 15–20 min in 37 °C incubator.…”

Effects of the estrous cycle and ovarian hormones on cue-triggered motivation and intrinsic excitability of medium spiny neurons in the Nucleus Accumbens of female rats

“…The reduction in excitability during proestrus/estrus vs. metestrus/diestrus within obesity-prone rats is consistent with the ability of estradiol to enhance I A , thereby reducing excitability in cultured hippocampal neurons (Zhang et al, 2015). Progesterone also increases during the proestrus phase, and progesterone can block voltage-gated sodium and calcium channels, resulting in decreased neuronal excitability (Kelley Mermelstein, 2011).…”