Academia de Fisiología, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Colonia Casco de Santo Tomás, Ciudad de México, México.
Sección de Estudios de Posgrado e Investigación de la Escuela Superior de Medicina del IPN, Plan de San Luis y Díaz Mirón, Colonia Casco de Santo Tomás, Ciudad de México, México.
Synapse. 2023 May;77(3):e22263. doi: 10.1002/syn.22263. Epub 2023 Feb 13.
Accumulating evidence indicates that insulin-mediated signaling in the brain may play important roles in regulating neuronal function. Alterations to insulin signaling are associated with the development of neurological disorders including Alzheimer's disease and Parkinson's disease. Also, hyperglycemia and insulin resistance have been associated with seizure activity and brain injury. In recent work, we found that insulin increased inhibitory GABA -mediated tonic currents in the prefrontal cortex (PFC). In this work, we used local field potential recordings and calcium imaging to investigate the effect of insulin on seizure-like activity in PFC slices. Seizure-like events (SLEs) were induced by perfusing the slices with magnesium-free artificial cerebrospinal fluid (ACSF) containing the proconvulsive compound 4-aminopyridine (4-AP). We found that insulin decreased the frequency, amplitude, and duration of SLEs as well as the synchronic activity of PFC neurons evoked by 4-AP. These insulin effects were mediated by the PI3K/Akt signaling pathway and mimicked by gaboxadol (THIP), a δ GABA receptor agonist. The effect of insulin on the number of SLEs was partially blocked by L-655,708, an inverse agonist with high selectivity for GABA receptors containing the α5 subunit. Our results suggest that insulin reduces neuronal excitability by an increase of GABAergic tonic currents. The physiological relevance of these findings is discussed.
越来越多的证据表明，大脑中胰岛素介导的信号转导可能在调节神经元功能方面发挥重要作用。胰岛素信号的改变与包括阿尔茨海默病和帕金森病在内的神经紊乱的发展有关。此外，高血糖和胰岛素抵抗与癫痫发作和脑损伤有关。在最近的工作中，我们发现胰岛素增加了前额叶皮层（PFC）中抑制性 GABA 介导的紧张性电流。在这项工作中，我们使用局部场电位记录和钙成像来研究胰岛素对 PFC 切片中癫痫样活动的影响。癫痫样事件（SLEs）通过用含有促惊厥化合物 4-氨基吡啶（4-AP）的无镁人工脑脊液（ACSF）灌流切片来诱导。我们发现，胰岛素降低了 SLE 的频率、幅度和持续时间，以及 4-AP 诱发的 PFC 神经元的同步活动。这些胰岛素作用是通过 PI3K/Akt 信号通路介导的，并且被 GABA 受体激动剂 gaboxadol（THIP）模拟。胰岛素对 SLE 数量的影响部分被 L-655,708 阻断，L-655,708 是一种 GABA 受体反向激动剂，对含有α5 亚基的 GABA 受体具有高选择性。我们的结果表明，胰岛素通过增加 GABA 能紧张性电流来降低神经元兴奋性。讨论了这些发现的生理相关性。
