Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109
eNeuro. 2021 Sep 2;8(5). doi: 10.1523/ENEURO.0324-21.2021. Print 2021 Sep-Oct.
Kisspeptin-expressing neurons in the anteroventral-periventricular nucleus (AVPV) are part of a neural circuit generating the gonadotropin-releasing hormone (GnRH) surge. This process is estradiol-dependent and occurs on the afternoon of proestrus in female mice. On proestrus, AVPV kisspeptin neurons express more kisspeptin and exhibit higher frequency action potentials and burst firing compared with diestrus, which is characterized by a pulsatile rather than a prolonged surge of GnRH secretion. We hypothesized changes in voltage-gated potassium conductances shape activity profiles of these cells in a cycle-dependent manner. Whole-cell voltage-clamp recordings of GFP-identified AVPV kisspeptin neurons in brain slices from diestrous and proestrous mice revealed three subcomponents of the voltage-sensitive K current: fast-transient slow-transient, and residual. During proestrus, the V of inactivation of the fast-transient current was depolarized and the amplitude of the slow-transient component was reduced compared with diestrus; the residual component was consistent across both stages. Computational models were fit to experimental data, including published estrous-cycle effects on other voltage-gated currents. Computer simulations suggest proestrus-typical K currents are suppressive compared with diestrus. Interestingly, larger T-type, persistent-sodium, and hyperpolarization-activated currents during proestrus compensate for this suppressive effect while also enabling postinhibitory rebound bursting. These findings suggest modulation of voltage-gated K and multiple subthreshold depolarizing currents across the negative to positive feedback transition maintain AVPV kisspeptin neuron excitability in response to depolarizing stimuli. These changes also enable firing in response to hyperpolarization, providing a net increase in neuronal excitability, which may contribute to activation of this population leading up to the preovulatory GnRH surge.
吻肽表达神经元位于前腹侧-室旁核（AVPV），是产生促性腺激素释放激素（GnRH）激增的神经回路的一部分。这个过程依赖于雌二醇，发生在雌性小鼠的发情前期下午。在发情前期，AVPV 吻肽神经元表达更多的吻肽，并表现出比发情期更高的动作电位频率和爆发放电，发情期的特点是 GnRH 分泌呈脉冲式而不是持续激增。我们假设电压门控钾电导的变化以周期依赖性的方式塑造这些细胞的活动模式。在发情前期和发情期的小鼠脑片中，对 GFP 鉴定的 AVPV 吻肽神经元进行全细胞膜片钳记录，揭示了电压敏感 K 电流的三个亚成分：快瞬态、慢瞬态和残留。在发情前期，快瞬态电流的失活 V 向去极化偏移，并且与发情期相比，慢瞬态成分的幅度降低；残留成分在两个阶段都是一致的。计算模型与实验数据拟合，包括发表的关于其他电压门控电流的发情周期效应。计算机模拟表明，与发情期相比，发情期典型的 K 电流具有抑制作用。有趣的是，发情期较大的 T 型、持续钠型和超极化激活电流补偿了这种抑制作用，同时也使抑制后爆发式爆发。这些发现表明，跨负反馈到正反馈转变的电压门控 K 和多种亚阈值去极化电流的调制维持了 AVPV 吻肽神经元对去极化刺激的兴奋性。这些变化还使神经元能够对超极化作出反应，从而导致神经元兴奋性的净增加，这可能有助于该群体的激活，导致促性腺激素释放激素的前排卵激增。
