Dept. of Physiology and Pharmacology, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan.
J Neurophysiol. 2010 Mar;103(3):1397-409. doi: 10.1152/jn.00877.2009. Epub 2010 Jan 13.
The central cholinergic system regulates both the circadian clock and sleep-wake cycle and may participate in the feedback control of vigilance states on neural excitability in the suprachiasmatic nucleus (SCN) that houses the circadian clock. Here we investigate the mechanisms for cholinergic modulation of SCN neuron excitability. Cell-attached recordings indicate that the nonspecific cholinergic agonist carbachol (CCh) inhibited 55% and excited 21% SCN neurons, leaving 24% nonresponsive. Similar response proportions were produced by two muscarinic receptor [muscarinic acetylcholine receptor (mAChR)] agonists, muscarine and McN-A-343 (M1/4 agonist), but not by two nicotinic receptor (nAChR) agonists, nicotine and choline (alpha7-nAChR agonist), which, however, produced similar response proportions. Whole cell and perforated-patch recordings indicate that CCh inhibition of firing was mediated by membrane hyperpolarization due to activation of background K(+) currents, which were sensitive to submillimolar concentrations of Ba(2+) and to millimolar concentrations of TEA. RT-PCR analysis demonstrated the presence of mRNA for M1 to M5 mAChRs in SCN. The CCh-induced hyperpolarization and activation of background K(+) currents were blocked by M4 antagonists and to a lesser degree by M1 antagonists but were insensitive to the antagonists for M2 or M3, suggesting the involvement of M4 and M1 mAChRs in mediating CCh inhibition of firing. CCh enhancement of firing was mediated by membrane depolarization, as a result of postsynaptic inhibition of background K(+) currents. The multiple actions of cholinergic modulation via multiple receptors and ion channels may allow acetylcholine to finely control SCN neuron excitability in different physiological settings.
中枢胆碱能系统调节昼夜节律和睡眠-觉醒周期，并可能参与对位于昼夜节律钟的视交叉上核（SCN）中警觉状态的神经兴奋性的反馈控制。在这里，我们研究了胆碱能调节 SCN 神经元兴奋性的机制。细胞附着记录表明，非特异性胆碱能激动剂卡巴胆碱（CCh）抑制了 55%的 SCN 神经元，兴奋了 21%的 SCN 神经元，使 24%的 SCN 神经元无反应。两种毒蕈碱受体[毒蕈碱乙酰胆碱受体（mAChR）]激动剂，毒蕈碱和 McN-A-343（M1/4 激动剂）产生了相似的反应比例，但两种烟碱受体（nAChR）激动剂，尼古丁和胆碱（α7-nAChR 激动剂）没有产生相似的反应比例，然而，它们产生了相似的反应比例。全细胞和穿孔贴片记录表明，CCh 抑制放电是通过激活背景 K(+)电流导致膜超极化介导的，背景 K(+)电流对亚毫摩尔浓度的 Ba(2+)和毫摩尔浓度的 TEA 敏感。RT-PCR 分析表明，SCN 中存在 M1 到 M5 mAChR 的 mRNA。CCh 诱导的超极化和背景 K(+)电流的激活被 M4 拮抗剂阻断，并且在较小程度上被 M1 拮抗剂阻断，但对 M2 或 M3 的拮抗剂不敏感，表明 M4 和 M1 mAChR 参与介导 CCh 抑制放电。CCh 增强放电是通过背景 K(+)电流的突触后抑制导致的膜去极化介导的。通过多种受体和离子通道的胆碱能调制的多种作用可能允许乙酰胆碱在不同的生理环境下精细地控制 SCN 神经元的兴奋性。
