Diurnal In Vivo and Rapid In Vitro Effects of Estradiol on Voltage-Gated Calcium Channels in Gonadotropin-Releasing Hormone Neurons

A robust surge of gonadotropin-releasing hormone (GnRH) release triggers the luteinizing hormone surge that induces ovulation. The GnRH surge is attributable to estradiol feedback, but the mechanisms are incompletely understood. Voltage-gated calcium channels (VGCCs) regulate hormone release and neuronal excitability, and may be part of the surge-generating mechanism. We examined VGCCs of GnRH neurons in brain slices from a model exhibiting daily luteinizing hormone surges. Mice were ovariectomized (OVX), and a subset was treated with estradiol implants (OVX + E). OVX + E mice exhibit negative feedback in the A. M. and positive feedback in the P.M. GnRH neurons express prominent high-voltage-activated (HVA) and small low-voltage-activated (LVA) macroscopic (whole-cell) Ca currents (I-Ca). LVA-mediated currents were not altered by estradiol or time of day. In contrast, in OVX + E mice, HVA-mediated currents varied with time of day; HVAcurrents in cells from OVX + E mice were lower than those in cells fromOVXmice in the A.M. but were higher in the P.M. These changes were attributable to diurnal alternations in L-and N-type components. There were no diurnal changes in any aspect of HVA-mediated I-Ca in OVX mice. Acute in vitro treatment of cells from OVX and OVX + E mice with estradiol rapidly increased HVA currents primarily through L-and R-type VGCCs by activating estrogen receptor beta and GPR30, respectively. These results suggest multiple mechanisms contribute to the overall feedback regulation of HVA-mediated I-Ca by estradiol. In combination with changes in synaptic inputs to GnRH neurons, these intrinsic changes in GnRH neurons may play critical roles in estradiol feedback.