Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia 22908, USA.
Endocrinology. 2010 Jan;151(1):291-300. doi: 10.1210/en.2009-0692. Epub 2009 Oct 30.
GnRH neurons are the final central pathway controlling fertility. Kisspeptin potently activates GnRH release via G protein-coupled receptor 54 (GPR54). GnRH neurons express GPR54, and kisspeptin can act directly; however, GPR54 is broadly expressed, suggesting indirect actions are possible. Transsynaptic mechanisms are involved in estradiol-induced potentiation of GnRH neuron response to kisspeptin. To investigate these mechanisms, separate whole-cell voltage-clamp recordings were performed of gamma-aminobutyric acid (GABA)-ergic and glutamatergic transmission to GnRH neurons in brain slices before and during kisspeptin treatment. To determine whether estradiol alters the effect of kisspeptin on synaptic transmission, mice were ovariectomized and either left with no further treatment (OVX) or treated with estradiol implants (OVX+E). Cells were first studied in the morning when estradiol exerts negative feedback. Kisspeptin increased frequency and amplitude of GABAergic postsynaptic currents (PSCs) in GnRH neurons from OVX+E mice. Blocking action potentials eliminated the effect on frequency, indicating presynaptic actions. Amplitude changes were due to postsynaptic actions. Kisspeptin also increased frequency of glutamatergic excitatory PSCs in cells from OVX+E animals. Kisspeptin did not affect either GABAergic or glutamatergic transmission to GnRH neurons in cells from OVX mice, indicating effects on transmission are estradiol dependent. In contrast to stimulatory effects on GABAergic PSC frequency during negative feedback, kisspeptin had no effect during positive feedback. These data suggest estradiol enables kisspeptin-mediated increases in GABA and glutamate transmission to GnRH neurons. Furthermore, the occlusion of the response during positive feedback implies one consequence of estradiol positive feedback is an increase in transmission to GnRH neurons mediated by endogenous kisspeptin.
GnRH 神经元是控制生育能力的最终中枢途径。促性腺激素释放激素（GnRH）通过 G 蛋白偶联受体 54（GPR54）强烈激活 GnRH 释放。GnRH 神经元表达 GPR54，促性腺激素释放激素可以直接作用；然而，GPR54 广泛表达，表明可能存在间接作用。突触前机制参与了雌激素诱导的 GnRH 神经元对促性腺激素释放激素反应的增强。为了研究这些机制，在给予促性腺激素释放激素前和期间，对脑切片中的 GABA 能和谷氨酸能传递到 GnRH 神经元进行了单独的全细胞电压钳记录。为了确定雌激素是否改变了促性腺激素释放激素对突触传递的影响，将小鼠去卵巢，不进行进一步治疗（OVX）或用雌激素植入物治疗（OVX+E）。当雌激素发挥负反馈作用时，细胞首先在早晨进行研究。促性腺激素释放激素增加了来自 OVX+E 小鼠的 GnRH 神经元中 GABA 能突触后电流（PSC）的频率和幅度。阻断动作电位消除了对频率的影响，表明存在突触前作用。幅度变化归因于突触后作用。促性腺激素释放激素还增加了来自 OVX+E 动物细胞中谷氨酸能兴奋性 PSC 的频率。促性腺激素释放激素对来自 OVX 小鼠的 GnRH 神经元的 GABA 能或谷氨酸能传递没有影响，表明传递的影响取决于雌激素。与负反馈期间对 GABA 能 PSC 频率的刺激作用相反，促性腺激素释放激素在正反馈期间没有影响。这些数据表明，雌激素使促性腺激素释放激素介导的 GABA 和谷氨酸传递增加到 GnRH 神经元。此外，正反馈期间对反应的阻断意味着雌激素正反馈的一个后果是，内源性促性腺激素释放激素介导的 GnRH 神经元传递增加。
