GLP-1 exerts its anorexigenic effect at least partly via the POMC neurons of the arcuate nucleus (ARC). These neurons are known to express GLP-1 receptor (GLP-1R). To determine whether in addition to its direct effect, GLP-1 also modulates, how neuronal inputs can regulate the POMC neurons by acting on presynaptic terminals, ultrastructural and electrophysiological studies were performed on tissues of adult male mice. GLP-1R-immunoreactivity was associated with the cell membrane of POMC neurons and with axon terminals forming synapses on these cells. The GLP-1 analog Exendin 4 (Ex4) markedly increased the firing rate of all examined POMC neurons and depolarized these cells. These effects of Ex4 were prevented by intracellular administration of the G-protein blocker GDP-β-S. Ex4 also influenced the miniature and evoked postsynaptic currents (PSCs) of POMC neurons. Ex4 increased the frequency of miniature excitatory PSCs and the amplitude of the evoked excitatory PSCs in half of the POMC neurons. Ex4 increased the frequency of miniature inhibitory PSCs and the amplitudes of the evoked inhibitory PSCs in one-third of neurons. These effects of Ex4 were not influenced by intracellular GDP-β-S, indicating that GLP-1-signaling directly stimulates a population of axon terminals innervating the POMC neurons. The different Ex4 responsiveness of their mPSCs indicates the heterogeneity of the POMC neurons of the ARC. In summary, our data demonstrate that in addition to its direct excitatory effect on the POMC neurons, GLP-1-signaling also facilitates the presynaptic input of these cells by acting on presynaptically localized GLP-1R.


中文翻译：

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GLP-1通过突触前作用直接和间接调节弓状核的POMC神经元

GLP-1 至少部分通过弓状核 (ARC) 的 POMC 神经元发挥其厌食作用。已知这些神经元表达 GLP-1 受体 (GLP-1R)。为了确定除了其直接作用之外，GLP-1 是否还调节神经元输入如何通过作用于突触前末端来调节 POMC 神经元，对成年雄性小鼠的组织进行了超微结构和电生理学研究。GLP-1R 免疫反应性与 POMC 神经元的细胞膜和在这些细胞上形成突触的轴突末端有关。GLP-1 模拟 Exendin 4 (Ex4) 显着增加了所有检查的 POMC 神经元的放电率并使这些细胞去极化。通过细胞内施用 G 蛋白阻滞剂 GDP-β-S 可以防止 Ex4 的这些作用。Ex4 还影响了 POMC 神经元的微型和诱发突触后电流 (PSC)。Ex4 增加了一半 POMC 神经元中微型兴奋性 PSC 的频率和诱发兴奋性 PSC 的幅度。Ex4 增加了三分之一神经元中微型抑制性 PSC 的频率和诱发抑制性 PSC 的幅度。Ex4 的这些作用不受细胞内 GDP-β-S 的影响，表明 GLP-1 信号传导直接刺激支配 POMC 神经元的轴突末端群。其 mPSC 的不同 Ex4 反应表明 ARC 的 POMC 神经元的异质性。总之，我们的数据表明，除了对 POMC 神经元的直接兴奋作用外，