Voltage-Gated Potassium Currents Are Targets of Diurnal Changes in Estradiol Feedback Regulation and Kisspeptin Action on Gonadotropin-Releasing Hormone Neurons in Mice

Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia, USA.
Biology of Reproduction (Impact Factor: 3.32). 07/2011; 85(5):987-95. DOI: 10.1095/biolreprod.111.093492
Source: PubMed


Estradiol has both negative and positive feedback actions upon gonadotropin-releasing hormone (GnRH) release; the latter actions trigger the preovulatory GnRH surge. Although neurobiological mechanisms of the transitions between feedback modes are becoming better understood, the roles of voltage-gated potassium currents, major contributors to neuronal excitability, are unknown. Estradiol alters two components of potassium currents in these cells: a transient current, I(A), and a sustained current, I(K). Kisspeptin is a potential mediator between estradiol and GnRH neurons and can act directly on GnRH neurons. We examined how estradiol, time of day, and kisspeptin interact to regulate these conductances in a mouse model exhibiting daily switches between estradiol negative (morning) and positive feedback (evening). Whole-cell voltage clamp recordings were made from GnRH neurons in brain slices from ovariectomized (OVX) mice and from OVX mice treated with estradiol (OVX+E). There were no diurnal changes in either I(A) or I(K) in GnRH neurons from OVX mice. In contrast, in GnRH neurons from OVX+E mice, I(A) and I(K) were greater during the morning when GnRH neuron activity is low and smaller in the evening when GnRH neuron activity is high. Estradiol increased I(A) in the morning and decreased it in the evening, relative to that in cells from OVX mice. Exogenously applied kisspeptin reduced I(A) regardless of time of day or estradiol status. Estradiol, interacting with time of day, and kisspeptin both depolarized I(A) activation. These findings extend our understanding of both the neurobiological mechanisms of estradiol negative vs. positive regulation of GnRH neurons and of kisspeptin action on these cells.

Download full-text


Available from: Justyna Pielecka-Fortuna, Sep 10, 2014
  • Source
    • "I K Yes Yes Herbison, 1998; 25 Pielecka-Fortuna et al., 2011 26 I M No No Xu et al., 2008 21 S K Yes No Bosch et al., 2003; 24 Kelly et al., 2002; 22 Kelly et al., 2003; 23 Kato et al., 2006; 29 Liu and Herbison, 2008; 13 Lee et al., 2010 30 B K No No Hiraizumi et al., 2008 31 KATP Yes No Zhang et al., 2007 27 Calcium L-type Yes Yes Nunemaker et al., 2003; 33 Sun et al., 2010 N-type Yes Yes Nunemaker et al., 2003; 33 Sun et al., 2010 P-type No No Nunemaker et al., 2003 33 Q-type No No Nunemaker et al., 2003 33 R-type Yes Yes Nunemaker et al., 2003; 33 Sun et al., 2010 T-type Yes No Kato et al., 2003; 34 Nunemaker et al., 2003; 33 Zhang et al., 2009 36 Chloride GABA A No No Weyler et al., 1999; Herbison and Moenter, 2011 38 Summary table of the ionic conductances described for GnRH neurons. Intrinsic GnRH conductances, estrogen sensitivity, and diurnal effects are listed per conductance type. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent findings indicate that a majority of action potentials originate from dendrites of GnRH neurons. This localization of the dendrite as the principle site of action potential initiation has sparked considerable interest in the nature of ionic channels throughout GnRH neurons. This paper will review the ionic conductances described within GnRH neurons and their implications for physiological output, such as sensitivity to steroids and diurnal state. To date, a majority of information regarding ionic conductances in GnRH neurons pertains to somata and the first 50-100 µm of dendrite length. Thus, unraveling the tapestry created by the nature and distribution of dendritic conductances in GnRH neurons lies at the forefront of understanding the control of reproductive hormone secretion.
    Full-text · Article · Mar 2013 · Channels (Austin, Tex.)
  • [Show abstract] [Hide abstract]
    ABSTRACT: GnRH neurons are critical for the central regulation of fertility, integrating steroidal, metabolic and other cues. GnRH neurons appear to lack receptors for many of these cues, suggesting involvement of afferent systems to convey information. Orexin A (orexin) is of interest in this regard as a neuromodulator that up-regulates metabolic activity, increases wakefulness, and affects GnRH/LH release. We examined the electrophysiological response of GnRH neurons to orexin application and how this response changes with estradiol and time of day in a defined animal model. Mice were either ovariectomized (OVX) or OVX and implanted with estradiol capsules (OVX+E). GnRH neurons from OVX+E mice exhibit low firing rates in the morning, due to estradiol-negative feedback, and high firing rates in the evening, due to positive feedback. Orexin inhibited activity of GnRH neurons from OVX mice independent of time of day. In GnRH neurons from OVX+E mice, orexin was inhibitory during the evening, suggesting orexin inhibition is not altered by estradiol. No effect of orexin was observed in OVX+E morning recordings, due to low basal GnRH activity. Inhibitory effects of orexin were mediated by the type 1 orexin receptor, but antagonism of this receptor did not increase GnRH neuron activity during estradiol-negative feedback. Spike pattern analysis revealed orexin increases interevent interval by reducing the number of single spikes and bursts. Orexin reduced spikes/burst and burst duration but did not affect intraburst interval. This suggests orexin may reduce overall firing rate by suppressing spike initiation and burst maintenance in GnRH neurons.
    No preview · Article · Jun 2012 · Endocrinology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Kisspeptin binding to its cognate G protein-coupled receptor (GPR54, aka Kiss1R) in gonadotropin-releasing hormone (GnRH) neurons stimulates peptide release and activation of the reproductive axis in mammals. Kisspeptin has pronounced pre- and postsynaptic effects, with the latter dominating the excitability of GnRH neurons. Presynaptically, kisspeptin increases the excitatory drive (both GABA-A and glutamate) to GnRH neurons and postsynaptically, kisspeptin inhibits an A-type and inwardly rectifying K(+) (Kir 6.2 and GIRK) currents and activates nonselective cation (TRPC) currents to cause long-lasting depolarization and increased action potential firing. The signaling cascades and the multiple intracellular targets of kisspeptin actions in native GnRH neurons are continuing to be elucidated. This review summarizes our current state of knowledge about kisspeptin signaling in GnRH neurons.
    No preview · Article · Apr 2013 · Advances in Experimental Medicine and Biology
Show more