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 to 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-inactivating, slow-inactivating, and residual. During proestrus, the V50 of inactivation of the fast-inactivating current was depolarized and the amplitude of the slow-inactivating component was reduced compared to 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 to diestrus. Interestingly, larger T-type, persistent-sodium, and hyperpolarization-activated currents during proestrus compensate for this suppressive effect while also enabling post-inhibitory 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.

Significance Statement

GnRH neurons provide the central signal to initiate ovulation by releasing a surge of hormone. GnRH neurons are regulated by other cells including those expressing kisspeptin, a potent stimulator of GnRH secretion. Kisspeptin neurons in the anteroventral-periventricular nucleus (AVPV) express more kisspeptin and become more active during the afternoon of proestrus, the phase of the rodent estrous (reproductive) cycle when the GnRH surge occurs. We found voltage-dependent potassium currents in AVPV kisspeptin neurons change with phase of the estrous cycle. Firing simulations indicated these changes are suppressive if occurring in isolation. But proestrous-typical increases in subthreshold depolarizing currents overcome this suppression and promote greater excitability by increasing rebound firing, possibly contributing to the preovulatory activation of this system.