Cholinergic activation of enteric glia is a physiological mechanism that contributes to the regulation of gastrointestinal motility
Cholinergic activation of enteric glia is a physiological mechanism that contributes to the regulation of gastrointestinal motility
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DOI：
10.1152/ajpgi.00155.2018
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发表时间：
2018-10-01
影响因子：
4.5
通讯作者：
Gulbransen, Brian D.
中科院分区：
文献类型：
--
作者：
Delvalle, Ninotchska M.;Fried, David E.;Gulbransen, Brian D.
胃肠道的反射活动部分地由肠神经系统（ENS）中神经元和胶质细胞之间的精确相互作用来调节。神经节内肠神经胶质细胞是一种独特类型的外周神经胶质细胞，其围绕肠神经元并调节神经元的功能、活性和存活。肠神经胶质细胞表达许多神经递质受体，使他们能够感知神经元的活动，但目前尚不清楚，如果肠神经胶质细胞监测乙酰胆碱（ACh），在ENS的主要兴奋性神经递质。在这里，我们测试的假设，肠神经胶质细胞检测ACh和神经胶质细胞激活ACh有助于肠道功能的生理调节。我们的研究结果表明，肌间肠神经胶质细胞表达M3和M5亚型的毒蕈碱受体（MR）和毒蕈碱驱动细胞内钙（Ca 2+）信号主要通过M3 R激活。为了阐明神经胶质M3 R激活的功能效应，我们使用仅在神经胶质酸性蛋白（GFAP）阳性神经胶质上表达修饰的人M3 R（hM 3Dq）的GFAP：：hM 3Dq小鼠，使用氯氮平-N-氧化物直接激活神经胶质hM 3Dq。使用时空映射分析，我们发现，神经胶质细胞hM 3Dq受体的激活增强运动反射离体。hM 3Dq受体在体内的连续刺激，在不影响神经元存活的ENS和胶质细胞毒蕈碱受体活化的胃肠动力的变化，并没有改变神经元存活在体外。我们的研究结果提供了第一个证据表明，GFAP神经节内肠神经胶质细胞表达功能性毒蕈碱受体，并表明，胶质细胞毒蕈碱受体的激活有助于生理调节的functions.NEW &值得注意的肠神经胶质细胞正在出现作为新的监管机构的肠反射circuits. NEW，但仍然知之甚少，关于特定的递质通路对神经胶质细胞的影响和由此产生的后果对肠反射。在这里，我们提供的第一个证据表明，肠神经胶质细胞监测乙酰胆碱在肠神经系统和神经胶质细胞激活乙酰胆碱是一种生理机制，有助于肠反射的功能调节。
The reflexive activities of the gastrointestinal tract are regulated, in part, by precise interactions between neurons and glia in the enteric nervous system (ENS). Intraganglionic enteric glia are a unique type of peripheral glia that surround enteric neurons and regulate neuronal function, activity, and survival. Enteric glia express numerous neurotransmitter receptors that allow them to sense neuronal activity, but it is not clear if enteric glia monitor acetylcholine (ACh), the primary excitatory neurotransmitter in the ENS. Here, we tested the hypothesis that enteric glia detect ACh and that glial activation by ACh contributes to the physiological regulation of gut functions. Our results show that myenteric enteric glia express both the M3 and M5 subtypes of muscarinic receptors (MRs) and that muscarine drives intracellular calcium (Ca2+) signaling predominantly through M3R activation. To elucidate the functional effects of activation of glial M3Rs, we used GFAP::hM3Dq mice that express a modified human M3R (hM3Dq) exclusively on glial fibrillary acidic protein (GFAP) positive glia to directly activate glial hM3Dqs using clozapine-N-oxide. Using spatiotemporal mapping analysis, we found that the activation of glial hM3Dq receptors enhances motility reflexes ex vivo. Continuous stimulation of hM3Dq receptors in vivo, drove changes in gastrointestinal motility without affecting neuronal survival in the ENS and glial muscarinic receptor activation did not alter neuron survival in vitro. Our results provide the first evidence that GFAP intraganglionic enteric glia express functional muscarinic receptors and suggest that the activation of glial muscarinic receptors contributes to the physiological regulation of functions.NEW & NOTEWORTHY Enteric glia are emerging as novel regulators of enteric reflex circuits, but little is still known regarding the effects of specific transmitter pathways on glia and the resulting consequences on enteric reflexes. Here, we provide the first evidence that enteric glia monitor acetylcholine in the enteric nervous system and that glial activation by acetylcholine is a physiological mechanism that contributes to the functional regulation of intestinal reflexes.