Estradiol Enhances the Depolarizing Response to GABA and AMPA Synaptic Conductances in Arcuate Kisspeptin Neurons by Diminishing Voltage-Gated Potassium Currents

Abstract

Synaptic and intrinsic properties interact to sculpt neuronal output. Kisspeptin neurons in the hypothalamic arcuate nucleus help convey homeostatic estradiol feedback to central systems controlling fertility. Estradiol increases membrane depolarization induced by GABA A receptor activation in these neurons. We hypothesized that the mechanisms underlying estradiol-induced alterations in postsynaptic response to GABA, and also AMPA, receptor activation include regulation of voltage-gated potassium currents. Whole-cell recordings of arcuate kisspeptin neurons in brain slices from ovariectomized (OVX) and OVXϩestradiol (OVXϩE) female mice during estradiol negative feedback revealed that estradiol reduced capacitance, reduced transient and sustained potassium currents, and altered voltage dependence and kinetics of transient currents. Consistent with these observations, estradiol reduced rheobase and action potential latency. To study more directly interactions between synaptic and active intrinsic estradiol feedback targets, dynamic clamp was used to simulate GABA and AMPA conductances. Both GABA and AMPA dynamic clamp-induced postsynaptic potentials (PSPs) were smaller in neurons from OVX than OVXϩE mice; blocking transient potassium currents eliminated this difference. To interrogate the role of the estradiol-induced changes in passive intrinsic properties, different Markov model structures based on the properties of the transient potassium current in cells from OVX or OVXϩE mice were combined in silico with passive properties reflecting these two endocrine conditions. Some of tested models reproduced the effect on PSPs in silico, revealing that AMPA PSPs were more sensitive to changes in capacitance. These observations support the hypothesis that PSPs in arcuate kisspeptin neurons are regulated by estradiol-sensitive mechanisms including potassium conductances and membrane properties.

Gonadotropin-Releasing Hormone (GnRH) Neuron Potassium Currents and Excitability in Both Sexes Exhibit Minimal Changes upon Removal of Negative Feedback

“…In KNDy neurons from OVX+E vs OVX females examined during negative feedback in the morning, estradiol reduced fast transient I A (DeFazio et al, 2019), and I A modifies action potential patterns in these cells (Mendonca et al, 2018).…”

“…For example, blocking a fraction of potassium channels with 4-aminopyridine (4AP) increases the excitability of motor neurons in amyotropic lateral sclerosis and multiple sclerosis and provides relief from the symptoms of these diseases (Bakirtzis et al, 2018;Peikert et al, 2019). In many neurons, 4AP increases input resistance and diminishes the ability of voltage-gated potassium channels to blunt action potential firing and/or the membrane potential changes in response to synaptic inputs (Hoffman, 2013;DeFazio et al, 2019). Here we tested the hypotheses that voltage-gated potassium currents are reduced and excitability of GnRH neurons increased by gonadectomy.…”

Lack of sex differences in gonadotropin-releasing hormone (GnRH) neuron potassium currents and excitability

“…KNDy neurons have been postulated to be key afferent inputs to GnRH neurons to drive episodic release from these cells (Qiu et al, 2016;Clarkson et al, 2017;Vanacker et al, 2017). In KNDy neurons from OVX+E vs OVX females examined during negative feedback in the morning, estradiol reduced fast transient IA (DeFazio et al, 2019), and IA modifies action potential patterns in these cells (Mendonca et al, 2018).…”

“…For example, blocking a fraction of potassium channels with 4-aminopyridine (4AP) increases the excitability of motor neurons in amyotropic lateral sclerosis and multiple sclerosis and provides relief from the symptoms of these diseases (Bakirtzis et al, 2018; Peikert et al, 2019). In many neurons, 4AP increases input resistance and diminishes the ability of voltage-gated potassium channels to blunt action potential firing and/or the membrane potential changes in response to synaptic inputs (Hoffman, 2013; DeFazio et al, 2019). Here we tested the hypotheses that voltage-gated potassium currents are reduced and excitability of GnRH neurons increased by gonadectomy in both sexes.…”

Reciprocal changes in voltage-gated potassium and subthreshold inward currents help maintain firing dynamics of AVPV kisspeptin neurons during the estrous cycle

“…Potassium currents, which strongly influence firing onset of many neurons and are vital for proper repolarization of the membrane (Hille, 2001), remained uncharacterized in AVPV kisspeptin neurons. K + currents change across the estrous cycle and in response to estradiol in GnRH neurons and kisspeptin neurons in the arcuate nucleus (DeFazio et al, , 2019Pielecka-Fortuna et al, 2011).…”