Shift in Kiss1 Cell Activity Requires Estrogen Receptor

Division of Hypothalamic Research, Department of Internal Medicine, Touchstone Diabetes Center, Department of Internal Medicine, and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2013; 33(7):2807-20. DOI: 10.1523/JNEUROSCI.1610-12.2013
Source: PubMed


Reproductive function requires timely secretion of gonadotropin-releasing hormone, which is controlled by a complex excitatory/inhibitory network influenced by sex steroids. Kiss1 neurons are fundamental players in this network, but it is currently unclear whether different conditions of circulating sex steroids directly alter Kiss1 neuronal activity. Here, we show that Kiss1 neurons in the anteroventral periventricular and anterior periventricular nuclei (AVPV/PeN) of males and females exhibit a bimodal resting membrane potential (RMP) influenced by K(ATP) channels, suggesting the presence of two neuronal populations defined as type I (irregular firing patterns) and type II (quiescent). Kiss1 neurons in the arcuate nucleus (Arc) are also composed of firing and quiescent cells, but unlike AVPV/PeN neurons, the range of RMPs did not follow a bimodal distribution. Moreover, Kiss1 neuronal activity in the AVPV/PeN, but not in the Arc, is sexually dimorphic. In females, estradiol shifts the firing pattern of AVPV/PeN Kiss1 neurons and alters cell capacitance and spontaneous IPSCs amplitude of AVPV/PeN and Arc Kiss1 populations in an opposite manner. Notably, mice with selective deletion of estrogen receptor α (ERα) from Kiss1 neurons show cellular activity similar to that observed in ovariectomized females, suggesting that estradiol-induced changes in Kiss1 cellular properties require ERα. We also show that female prepubertal Kiss1 neurons are under higher inhibitory influence and all recorded AVPV/PeN Kiss1 neurons were spontaneously active. Collectively, our findings indicate that changes in cellular activity may underlie Kiss1 action in pubertal initiation and female reproduction.

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Available from: Kevin W Williams, Feb 11, 2014
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    • "RMP $ GDX = $ GDX + E 2 (Frazao et al., 2013) $ GDX + low E 2 = $ GDX + high E 2 (Zhang et al., 2013c) $ GDX = $ diestrus = $ proestrus (Piet et al., 2013) Capacitance $ GDX < $ GDX + E 2 (Frazao et al., 2013) $ GDX + low E 2 = $ GDX + high E 2 (Zhang et al., 2013c) $ GDX < $ diestrus = $ proestrus (Piet et al., 2013) R in $ GDX > $ diestrus > $ proestrus (Piet et al., 2013) Rheobase $ GDX = $ diestrus = $ proestrus (Piet et al., 2013) AP half-duration $ GDX > $ diestrus > $ proestrus (Piet et al., 2013) Spontaneous firing $ GDX < $ diestrus = $ proestrus (de Croft et al., 2012) $ GDX = $ GDX + E 2 (Frazao et al., 2013) I h $ GDX < $ diestrus < $ proestrus (Piet et al., 2013) $ GDX + low E 2 < $ GDX + high E 2 (Zhang et al., 2013c) I T $ GDX + low E 2 < $ GDX + high E 2 (Zhang et al., 2013c) Spontaneous GABA and glutamate transmission (sEPSC and sIPSC amplitude, frequency and kinetics) $ GDX = $ diestrus = $ proestrus (Piet et al., 2013) sIPSC amplitude $ GDX < $ GDX + E 2 (Frazao et al., 2013) "
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    ABSTRACT: Kisspeptin neurons are critical components of the neuronal network controlling the activity of the gonadotropin-releasing hormone (GnRH) neurons. A variety of genetically-manipulated mouse models have recently facilitated the study of the electrical activity of the two principal kisspeptin neuron populations located in the rostral periventricular area of the third ventricle (RP3V) and arcuate nucleus (ARN) in acute brain slices. We discuss here the mechanisms and pathways through which kisspeptin neurons regulate GnRH neuron activity. We then examine the different kisspeptin-green fluorescent protein mouse models being used for kisspeptin electrophysiology and the data obtained to date for RP3V and ARN kisspeptin neurons. In light of these new observations on the spontaneous firing rates, intrinsic membrane properties, and neurotransmitter regulation of kisspeptin neurons, we speculate on the physiological roles of the different kisspeptin populations.
    Frontiers in Neuroendocrinology 06/2014; 36. DOI:10.1016/j.yfrne.2014.05.006 · 7.04 Impact Factor
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    ABSTRACT: Pulsatile GnRH release is essential to fertility and is modulated by gonadal steroids, most likely via steroid-sensitive afferents. Arcuate neurons coexpressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy neurons) are steroid-sensitive and have been postulated to both generate GnRH pulses and mediate steroid feedback on pulse frequency. KNDy neurons are proposed to interact with one another via NKB and dynorphin to activate and inhibit the KNDy network, respectively, and thus alter kisspeptin output to GnRH neurons. To test the roles of NKB and dynorphin on KNDy neurons and the steroid sensitivity of these actions, targeted extracellular recordings were made of Tac2(NKB)-GFP-identified neurons from castrate and intact male mice. Single-cell PCR confirmed most of these cells had a KNDy phenotype. The neurokinin-3 receptor (NK3R) agonist senktide increased action potential firing activity of KNDy neurons. Dynorphin reduced spontaneous KNDy neuron activity, but antagonism of κ-opioid receptors (KOR) failed to induce firing activity in quiescent KNDy neurons. Senktide-induced activation was greater in KNDy neurons from castrate mice, whereas dynorphin-induced suppression was greater in KNDy neurons from intact mice. Interactions of dynorphin with senktide-induced activity were more complex; dynorphin treatment after senktide had no consistent inhibitory effect, whereas pretreatment with dynorphin decreased senktide-induced activity only in KNDy neurons from intact but not castrate mice. These data suggest dynorphin-mediated inhibition of senktide-induced activity requires gonadal steroid feedback. Together, these observations support the hypotheses that activation of NK3R and KOR, respectively, excites and inhibits KNDy neurons and that gonadal steroids modulate these effects.
    Endocrinology 06/2013; 154(8). DOI:10.1210/en.2013-1268 · 4.50 Impact Factor
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    ABSTRACT: Circulating gonadal steroid hormones are thought to modulate a wide range of brain functions. However, the effects of steroid fluctuations through the ovarian cycle on the intrinsic properties of neurons are not well understood. We examined here whether gonadal steroids modulated the excitability of kisspeptin neurons located in the rostral periventricular region of the third ventricle (RP3V) of female mice. These cells are strongly implicated in sensing the high levels of circulating estradiol on proestrus to activate gonadotropin-releasing hormone (GnRH) neurons that, in turn, trigger ovulation. Electrophysiological studies were undertaken in brain slices from ovariectomized (OVX), diestrous, and proestrous kisspeptin-GFP mice. RP3V kisspeptin neurons exhibited marked changes in the hyperpolarization-evoked depolarizing sag and rebound firing across these groups. The hyperpolarization-activated current Ih was identified to be responsible for the depolarizing sag and was increased across OVX → diestrous → proestrous mice. Experiments in OVX mice given estradiol replacement identified an estradiol-dependent increase in Ih within RP3V kisspeptin neurons. Ih in these cells was found to contribute to their subthreshold membrane properties and the dynamics of rebound firing following hyperpolarizing stimuli in an estrous cycle-dependent manner. Only a minor role was found for Ih in modulating the spontaneous burst firing of RP3V kisspeptin neurons. These observations identify Ih as an ionic current that is regulated in a cyclical manner by circulating estradiol within the female brain, and suggest that such plasticity in the intrinsic properties of RP3V kisspeptin neurons may contribute to the generation of the preovulatory GnRH surge.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 06/2013; 33(26):10828-10839. DOI:10.1523/JNEUROSCI.1021-13.2013 · 6.34 Impact Factor
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