Introduction: Hypophysiotropic gonadotropin releasing-hormone (GnRH) neurons orchestrate various physiological events that control the onset of puberty. Previous studies showed that insulin-like growth factor 1 (IGF-1) induces the secretion of GnRH and accelerates the onset of puberty, suggesting a regulatory role of this hormone upon GnRH neurons. Methods: To reveal responsiveness of GnRH neurons to IGF-1 and elucidate molecular pathways acting downstream to the IGF-1 receptor (IGF-1R), in vitro electrophysiological experiments were carried out on GnRH-GFP neurons in acute brain slices from prepubertal (23-29 days) and pubertal (50-day) male mice. Results: Administration of IGF-1 (13 nM) significantly increased the firing rate and frequency of spontaneous postsynaptic currents (sPSCs), and that of excitatory GABAergic miniature postsynaptic currents (mPSCs). No GABAergic mPSCs were induced by IGF-1 in the presence of GABAA-R blocker picrotoxin. The increase in the mPSC frequency was prevented by the use of IGF-1R antagonist, JB1 (1 µM) or the intracellularly applied PI3K blocker (LY294002, 50 µM) showing involvement of IGF-1R and PI3K in the mechanism. Blockade of the transient receptor potential vanilloid 1 (TRPV1), an element of the tonic retrograde endocannabinoid machinery by AMG9810 (10 µM) or antagonizing cannabinoid receptor type-1 (CB1) by AM251 (1 µM) abolished the effect. Discussion/Conclusion: These findings indicate that IGF-1 arrests the tonic retrograde endocannabinoid pathway in GnRH neurons and this disinhibition increases the release of GABA from presynaptic terminals that, in turn, activates GnRH neurons leading to the fine-tuning of the hypothalamo-pituitary-gonadal axis.


中文翻译：

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胰岛素样生长因子 1 (IGF-1) 通过抑制小鼠逆行强直性内源性大麻素信号通路增加 GnRH 神经元的 GABA 能神经传递

简介：低生理性促性腺激素释放激素 (GnRH) 神经元协调控制青春期开始的各种生理事件。先前的研究表明，胰岛素样生长因子 1 (IGF-1) 可诱导 GnRH 的分泌并加速青春期的开始，这表明这种激素对 GnRH 神经元具有调节作用。方法：为了揭示 GnRH 神经元对 IGF-1 的反应性并阐明作用于 IGF-1 受体 (IGF-1R) 下游的分子途径，对青春期前急性脑切片中的 GnRH-GFP 神经元进行体外电生理实验 (23 -29 天）和青春期（50 天）雄性小鼠。结果：施用 IGF-1 (13 nM) 显着增加了自发突触后电流 (sPSC) 的放电率和频率，和兴奋性 GABAergic 微型突触后电流 (mPSC)。在存在 GABAA-R 阻滞剂印防己毒素的情况下，IGF-1 没有诱导 GABAergic mPSCs。使用 IGF-1R 拮抗剂 JB1 (1 µM) 或细胞内应用的 PI3K 阻滞剂 (LY294002, 50 µM) 可防止 mPSC 频率的增加，显示 IGF-1R 和 PI3K 参与该机制。瞬时受体电位香草素 1 (TRPV1) 是 AMG9810 (10 µM) 补品逆行内源性大麻素机制的一个元素，或 AM251 (1 µM) 拮抗大麻素受体 1 型 (CB1) 可消除这种效果。讨论/结论：这些发现表明 IGF-1 阻止了 GnRH 神经元中的强直逆行内源性大麻素通路，这种去抑制增加了 GABA 从突触前末端的释放，反过来，