Department of Neurological Surgery, Houston Methodist Hospital, Houston, TX 77030, United States of America.
Department of Pulmonology and Critical Care Medicine, Houston Methodist Hospital, Houston, TX 77030, United States of America.
Mol Cell Neurosci. 2019 Oct;100:103400. doi: 10.1016/j.mcn.2019.103400. Epub 2019 Aug 28.
Several studies have investigated the general role of chloride-based neurotransmission (GABA and glycinergic signaling) in respiratory rhythmogenesis and pattern formation. In several brain regions, developmental alterations in these signaling pathways have been shown to be mediated by changes in cation-chloride cotransporter (CC) expression. For instance, CC expression changes during the course of neonatal development in medullary respiratory nuclei and other brain/spinal cord regions in a manner which decreases the cellular import, and increases the export, of chloride ions, shifting reversal potentials for chloride to progressively more negative values with maturation. In slice preparations of the same, this is related to an excitatory-to-inhibitory shift of GABA- and glycinergic signaling. In medullary slices, GABA-/glycinergic signaling in the early neonatal period is excitatory, becoming inhibitory over time. Additionally, blockade of the Na/K/2Cl cotransporter, which imports these ions via secondary active transport, converts excitatory response to inhibitory ones. These effects have not yet been demonstrated at the individual respiratory-related neuron level to occur in intact (in vivo or in situ) animal preparations, which in contrast to slices, possess normal network connectivity and natural sources of tonic drive. Developmental changes in respiratory rhythm generating and pattern forming pontomedullary respiratory circuitry may contribute to critical periods, during which there exist increased risk for perinatal respiratory disturbances of central, obstructive, or hypoxia/hypercapnia-induced origin, including the sudden infant death syndrome. Thus, better characterizing the neurochemical maturation of the central respiratory network will enhance our understanding of these conditions, which will facilitate development of targeted therapies for respiratory disturbances in neonates and infants.
已有多项研究探讨了基于氯离子的神经递质传递（GABA 和甘氨酸能信号）在呼吸节律产生和模式形成中的一般作用。在许多脑区中，这些信号通路的发育变化是通过阳离子-氯离子共转运蛋白（CC）表达的变化来介导的。例如，在延髓呼吸核和其他脑/脊髓区域，CC 表达在新生儿发育过程中发生变化，从而减少氯离子的细胞内摄取，增加氯离子的外排，使氯离子的反转电位随成熟而逐渐向更负的数值偏移。在相同的切片制备中，这与 GABA 和甘氨酸能信号从兴奋性到抑制性的转变有关。在延髓切片中，早期新生儿期的 GABA-和甘氨酸能信号是兴奋性的，随着时间的推移变得抑制性。此外，阻断 Na/K/2Cl 共转运体（通过次级主动转运来摄取这些离子），将兴奋性反应转化为抑制性反应。这些作用尚未在完整（体内或原位）动物准备中在单个与呼吸相关的神经元水平上得到证明，与切片不同，完整的动物准备具有正常的网络连接和自然的紧张驱动源。呼吸节律产生和模式形成 pontomedullary 呼吸回路的发育变化可能导致关键期的出现，在此期间，存在增加的风险，出现源于中枢、阻塞或缺氧/高碳酸血症的围产期呼吸障碍，包括婴儿猝死综合征。因此，更好地描述中枢呼吸网络的神经化学成熟将增强我们对这些情况的理解，这将有助于为新生儿和婴儿的呼吸障碍开发靶向治疗。
