Reciprocal Changes in Voltage-Gated Potassium and Subthreshold Inward Currents Help Maintain Firing Dynamics of AVPV Kisspeptin Neurons during the Estrous Cycle

Abstract

Kisspeptin-expressing neurons in the anteroventral-periventricular nucleus (AVPV) are part of a neural circuit generating the gonadotropin-releasing hormone (GnRH) surge. This process is estradiol-dependent and occurs on the afternoon of proestrus in female mice. On proestrus, AVPV kisspeptin neurons express more kisspeptin and exhibit higher frequency action potentials and burst firing compared with diestrus, which is characterized by a pulsatile rather than a prolonged surge of GnRH secretion. We hypothesized changes in voltage-gated potassium conductances shape activity profiles of these cells in a cycle-dependent manner. Whole-cell voltage-clamp recordings of GFP-identified AVPV kisspeptin neurons in brain slices from diestrous and proestrous mice revealed three subcomponents of the voltage-sensitive K + current: fast-transient slow-transient, and residual. During proestrus, the V 50 of inactivation of the fast-transient current was depolarized and the amplitude of the slow-transient component was reduced compared with diestrus; the residual component was consistent across both stages. Computational models were fit to experimental data, including published estrous-cycle effects on other voltage-gated currents. Computer simulations suggest proestrus-typical K + currents are suppressive compared with diestrus. Interestingly, larger T-type, persistent-sodium, and hyperpolarization-activated currents during proestrus compensate for this suppressive effect while also enabling postinhibitory rebound bursting. These findings suggest modulation of voltage-gated K + and multiple subthreshold depolarizing currents across the negative to positive feedback transition maintain AVPV kisspeptin neuron excitability in response to depolarizing stimuli. These changes also enable firing in response to hyperpolarization, providing a net increase in neuronal excitability, which may contribute to activation of this population leading up to the preovulatory GnRH surge.

Neuroendocrine mechanisms underlying estrogen positive feedback and the LH surge

“…Finally, as discussed further below, the LH surge is gated by a circadian clock (de la Iglesia and Schwartz, 2006), and RP3V KISS neurons display a circadian pattern of neuronal activation in perfect synchrony with the timing of the LH surge (Robertson et al, 2009). Additional electrophysiological evidence that supports that RP3V KISS neurons are positively regulated by estrogen, including reported stimulatory effects on ion currents in these cells in mice (Piet et al, 2013;Zhang et al, 2015;Wang et al, 2016;Starrett et al, 2021). Collectively, such studies conclude that normal estrous cycle-driven rises in circulating E 2 induce increases in overall action potential generation and burst firing in RP3V KISS neurons on proestrus (when E 2 is elevated) by regulating multiple intrinsic currents in these kisspeptin cells (Wang et al, 2016).…”