Estrous cycle plasticity in the hyperpolarization-activated current ih is mediated by circulating 17β-estradiol in...

Circulating gonadal steroid hormones are thought to modulate a wide range of brain functions. However, the effects of steroid fluctuations through the ovarian cycle on the intrinsic properties of neurons are not well understood. We examined here whether gonadal steroids modulated the excitability of kisspeptin neurons located in the rostral periventricular region of the third ventricle (RP3V) of female mice. These cells are strongly implicated in sensing the high levels of circulating estradiol on proestrus to activate gonadotropin-releasing hormone (GnRH) neurons that, in turn, trigger ovulation. Electrophysiological studies were undertaken in brain slices from ovariectomized (OVX), diestrous, and proestrous kisspeptin-GFP mice. RP3V kisspeptin neurons exhibited marked changes in the hyperpolarization-evoked depolarizing sag and rebound firing across these groups. The hyperpolarization-activated current Ih was identified to be responsible for the depolarizing sag and was increased across OVX → diestrous → proestrous mice. Experiments in OVX mice given estradiol replacement identified an estradiol-dependent increase in Ih within RP3V kisspeptin neurons. Ih in these cells was found to contribute to their subthreshold membrane properties and the dynamics of rebound firing following hyperpolarizing stimuli in an estrous cycle-dependent manner. Only a minor role was found for Ih in modulating the spontaneous burst firing of RP3V kisspeptin neurons. These observations identify Ih as an ionic current that is regulated in a cyclical manner by circulating estradiol within the female brain, and suggest that such plasticity in the intrinsic properties of RP3V kisspeptin neurons may contribute to the generation of the preovulatory GnRH surge.