Rapid Communication: 17β-Estradiol Increases Persistent Na+ Current and Excitability of AVPV/PeN Kiss1 Neurons in Female Mice

In vitro slice studies have revealed that there are significant differences in the spontaneous firing activity between anteroventral periventricular/periventricular preoptic nucleus (AVPV/PeN) and arcuate nucleus (ARC) kisspeptin (Kiss1) neurons in females. Although both populations express similar endogenous conductances, we have discovered that AVPV/PeN Kiss1 neurons express a subthreshold, persistent sodium current (I-NaP) that dramatically alters their firing activity. Based on whole-cell recording of Kiss1-Cre-green fluorescent protein (GFP) neurons, I-NaP was 4-fold greater in AVPV/PeN vs ARC Kiss1 neurons. An LH surge-producing dose of 17 beta-estradiol (E2) that increased Kiss1 mRNA expression in the AVPV/PeN, also augmented I-NaP in AVPV/PeN neurons by 2-fold. Because the activation threshold for I-NaP was close to the resting membrane potential (RMP) of AVPV/PeN Kiss1 neurons (-54 mV), it rendered them much more excitable and spontaneously active vs ARC Kiss1 neurons (RMP = -66 mV). Single-cell RT-PCR revealed that AVPV/PeN Kiss1 neurons expressed the requisite sodium channel alpha-subunit transcripts, Na(V)1.1, Na(V)1.2, and Na(V)1.6 and beta subunits, beta 2 and beta 4. Importantly, Na(V)1.1 alpha and -beta 2 transcripts in AVPV/PeN, but not ARC, were up-regulated 2- to 3-fold by a surge-producing dose of E2, similar to the transient calcium current channel subunit Ca-v 3.1. The transient calcium current collaborates with I-NaP to generate burst firing, and selective blockade of I-NaP by riluzole significantly attenuated rebound burst firing and spontaneous activity. Therefore, I-NaP appears to play a prominent role in AVPV/PeN Kiss1 neurons to generate spontaneous, repetitive burst firing, which is required for the high-frequency-stimulated release of kisspeptin for exciting GnRH neurons and potentially generating the GnRH surge.