Arizona College of Osteopathic Medicine, Midwestern University, Glendale, Arizona, United States.
Department of Physiology, College of Graduate Studies, Midwestern University, Glendale, Arizona, United States.
J Appl Physiol (1985). 2023 Nov 1;135(5):1041-1052. doi: 10.1152/japplphysiol.00042.2023. Epub 2023 Sep 28.
In neonatal rhythmic medullary slices, muscarinic acetylcholine receptor (mAChR) activation of hypoglossal (XII) motoneurons that innervate the tongue has a net excitatory effect on XII inspiratory motor output. Conversely, during rapid eye movement sleep in adult rodents, XII motoneurons experience a loss of excitability partly due to activation of mAChRs. This may be mediated by activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels. Therefore, this study was designed to evaluate whether muscarinic modulation of XII inspiratory motor output in mouse rhythmic medullary slices includes GIRK channel-mediated inhibition and, if so, when this inhibitory mechanism emerges. Local pressure injection of the mAChR agonist muscarine potentiated inspiratory bursting by 150 ± 28% in ()- rhythmic medullary slice preparations. In the absence of muscarine, pharmacological GIRK channel block by Tertiapin-Q did not affect inspiratory burst parameters, whereas activation with ML297 decreased inspiratory burst area. Blocking GIRK channels by local preapplication of Tertiapin-Q revealed a developmental change in muscarinic modulation of inspiratory bursting. In - rhythmic medullary slices, Tertiapin-Q preapplication had no significant effect on muscarinic potentiation of inspiratory bursting (a negligible 6% decrease). However, preapplication of Tertiapin-Q to - rhythmic medullary slices caused a 19% increase in muscarinic potentiation of XII inspiratory burst amplitude. Immunofluorescence experiments revealed expression of GIRK 1 and 2 subunits and M1, M2, M3, and M5 mAChRs from to . Overall, these data support that mechanisms underlying muscarinic modulation of inspiratory burst activity change postnatally and that potent GIRK-mediated inhibition described in adults emerges early in postnatal life. Muscarinic modulation of inspiratory bursting at hypoglossal motoneurons has a net excitatory effect in neonatal rhythmic medullary slice preparations and a net inhibitory effect in adult animals. We demonstrate that muscarinic modulation of inspiratory bursting undergoes maturational changes from to that include emergence of an inhibitory component mediated by G-protein-coupled inwardly rectifying potassium channels after in neonatal mouse rhythmic medullary slice preparations.
在新生儿节律性延髓切片中，支配舌部的舌下神经（XII）运动神经元上的毒蕈碱型乙酰胆碱受体（mAChR）的激活对 XII 吸气运动输出具有净兴奋作用。相反，在成年啮齿动物的快速眼动睡眠期间，XII 运动神经元的兴奋性部分丧失，这部分是由于 mAChR 的激活。这可能是由 G 蛋白偶联内向整流钾（GIRK）通道的激活介导的。因此，本研究旨在评估在小鼠节律性延髓切片中，毒蕈碱对 XII 吸气运动输出的调制是否包括 GIRK 通道介导的抑制，如果是，这种抑制机制何时出现。在（）-节律性延髓切片制剂中，局部加压注射 mAChR 激动剂毒蕈碱可使吸气爆发增强 150±28%。在没有毒蕈碱的情况下，用 Tertiapin-Q 进行药理学 GIRK 通道阻断对吸气爆发参数没有影响，而用 ML297 激活则降低吸气爆发面积。用 Tertiapin-Q 局部预应用阻断 GIRK 通道揭示了毒蕈碱对吸气爆发调制的发育变化。在-节律性延髓切片中，Tertiapin-Q 预应用对毒蕈碱增强吸气爆发没有显著影响（仅有可忽略不计的 6%的减少）。然而，将 Tertiapin-Q 预应用于-节律性延髓切片会导致 XII 吸气爆发幅度的毒蕈碱增强增加 19%。免疫荧光实验显示 GIRK1 和 2 亚基以及 M1、M2、M3 和 M5 mAChR 从到表达。总体而言，这些数据支持这样的观点，即毒蕈碱对吸气爆发活动的调制机制在出生后发生变化，并且在成年动物中描述的强 GIRK 介导的抑制作用在出生后早期出现。毒蕈碱对舌下运动神经元吸气爆发的调制在新生儿节律性延髓切片制剂中具有净兴奋作用，而在成年动物中具有净抑制作用。我们证明，从到，吸气爆发的毒蕈碱调制会发生发育变化，包括在新生儿小鼠节律性延髓切片制剂中，在出生后出现由 G 蛋白偶联内向整流钾通道介导的抑制成分。
