Department of Physiology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 226-8511, Japan.
Department of Physiology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 226-8511, Japan.
Neuroscience. 2017 Sep 30;360:139-145. doi: 10.1016/j.neuroscience.2017.07.025. Epub 2017 Jul 21.
Prostaglandin E2 (PGE2) promotes gonadotropin secretion by regulating the activity of neurons that release gonadotropin-releasing hormone (GnRH) in the hypothalamus. However, the mechanisms of action of PGE2 at these neurons have yet to be fully explored. We examined the effects of PGE2 on the generation of miniature excitatory postsynaptic currents (mEPSCs) at GnRH neurons as measured by whole-cell, patch-clamp recordings. GnRH neurons were identified in slices prepared from the preoptic areas of female GnRH-EGFP rats. Exposure to PGE2 significantly increased the frequency, but not the amplitude, of the mEPSCs generated on the day of proestrus, but neither frequency nor amplitude was altered on day 1 of diestrus. These data suggest that the action of PGE2 on mEPSC frequency varies depending on the stage of estrous. An estrogen-dependence of PGE2's action was further supported by the increased frequency, but not amplitude, of mEPSCs generated at GnRH neurons prepared from estrogen-primed ovariectomized rats. Conversely, PGE2 had no effect on mEPSC frequency or amplitude at GnRH neurons in cholesterol-treated rats. Subsequent experiments to identify candidate receptors for PG2E's action revealed that exposure to a PGE2 receptor 4 (EP4) agonist, but not EP1 or EP2 agonists, mimicked the effects achieved by PGE2 exposure. These effects of mEPSCs could be reversed using an EP4 antagonist, illustrating the specificity of the effect. Collectively, these data demonstrate that PGE2 can alter excitatory synaptic neurotransmission at GnRH neurons via EP4 signaling at presynaptic site(s) in an estrogen-dependent fashion during proestrus.
前列腺素 E2（PGE2）通过调节下丘脑释放促性腺激素释放激素（GnRH）的神经元的活性来促进促性腺激素的分泌。然而，PGE2 在这些神经元中的作用机制尚未得到充分探索。我们通过全细胞膜片钳记录检查了 PGE2 对 GnRH 神经元产生的微小兴奋性突触后电流（mEPSC）的产生的影响。GnRH 神经元是从雌性 GnRH-EGFP 大鼠的视前区切片中鉴定的。在发情前期，PGE2 的暴露显著增加了 mEPSC 的频率，但不改变其幅度，而在发情期第 1 天，频率和幅度都没有改变。这些数据表明，PGE2 对 mEPSC 频率的作用随动情期的阶段而变化。PGE2 作用的雌激素依赖性进一步得到支持，即在雌激素预处理的卵巢切除大鼠制备的 GnRH 神经元上产生的 mEPSC 的频率增加，但幅度不变。相反，在胆固醇处理的大鼠中，PGE2 对 GnRH 神经元的 mEPSC 频率或幅度没有影响。随后的实验以确定 PG2E 作用的候选受体表明，暴露于 PGE2 受体 4（EP4）激动剂，但不是 EP1 或 EP2 激动剂，模拟了 PGE2 暴露的效果。使用 EP4 拮抗剂可以逆转 mEPSC 的这些作用，说明了该作用的特异性。总之，这些数据表明，在发情前期，PGE2 可以通过雌激素依赖的方式通过 EP4 信号在突触前部位改变 GnRH 神经元的兴奋性突触传递。
