Gonadotropin-Releasing Hormone (GnRH) Neuron Excitability Is Regulated by Estradiol Feedback and Kisspeptin
Gonadotropin-Releasing Hormone (GnRH) Neuron Excitability Is Regulated by Estradiol Feedback and Kisspeptin
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DOI：
10.1523/jneurosci.2988-17.2017
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发表时间：
2018-01-31
影响因子：
5.3
通讯作者：
Moenter, Suzanne M.
中科院分区：
文献类型：
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作者：
Adams, Caroline;Stroberg, Wylie;Moenter, Suzanne M.
促性腺激素释放激素(GnRH)神经元产生控制生育的中枢输出，并受类固醇反馈调节。从雌二醇负反馈到正反馈的转换会引发GnRH激增，最终触发排卵。在卵巢切除、雌激素治疗(OVX+E)的小鼠中，这种情况每天都会发生；GnRH神经元在早上受到抑制，在下午被激活。为了验证雌激素和时间信号改变GnRH神经元对刺激的反应性的假设，我们在上午或下午记录了OVX+E或OVX雌性小鼠脑片中GFP识别的GnRH神经元。基线膜电位无明显差异。电流钳显示，在正反馈期间，GnRH神经元相对于所有其他组激发了更多的动作电位，作为对电流注入的反应，尽管有不同的离子电导的报道，但它们之间并没有什么不同。Kisspeptin在上午增加了OVX和OVX+E小鼠细胞中GnRH神经元的反应，但下午没有。矛盾的是，Kispeptin基因敲除小鼠的兴奋性与对照组小鼠的最大兴奋性相似，但不受一天中的时间或雌二醇的影响。应用马尔科夫链蒙特卡罗方法估计雌二醇和一天中时间相关参数的概率分布的数学模型被用来预测兴奋性变化的内在特性。除正反馈外，尽管基础电导特性不同，但在所有组中，单一可识别的溶液分布解释了相似的GnRH神经元兴奋性；这可归因于电压门控钾通道特性的相互依赖。相比之下，多余的解决方案可能解释了正反馈，或许表明了这种状态对物种生存的重要性。
Gonadotropin-releasing hormone (GnRH) neurons produce the central output controlling fertility and are regulated by steroid feedback. A switch from estradiol negative to positive feedback initiates the GnRH surge, ultimately triggering ovulation. This occurs on a daily basis in ovariectomized, estradiol-treated (OVX + E) mice; GnRH neurons are suppressed in the morning and activated in the afternoon. To test the hypotheses that estradiol and time of day signals alter GnRH neuron responsiveness to stimuli, GFP-identified GnRH neurons in brain slices from OVX + E or OVX female mice were recorded during the morning or afternoon. No differences were observed in baseline membrane potential. Current-clamp revealed GnRH neurons fired more action potentials in response to current injection during positive feedback relative to all other groups, which were not different from each other despite reports of differing ionic conductances. Kisspeptin increased GnRH neuron response in cells from OVX and OVX + E mice in the morning but not afternoon. Paradoxically, excitability in kisspeptin knock-out mice was similar to the maximum observed in control mice but was unchanged by time of day or estradiol. A mathematical model applying a Markov Chain Monte Carlo method to estimate probability distributions for estradiol-and time of day-dependent parameters was used to predict intrinsic properties underlying excitability changes. A single identifiable distribution of solutions accounted for similar GnRH neuron excitability in all groups other than positive feedback despite different underlying conductance properties; this was attributable to interdependence of voltage-gated potassium channel properties. In contrast, redundant solutions may explain positive feedback, perhaps indicative of the importance of this state for species survival.