Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons.
Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons.
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DOI：
10.1523/jneurosci.6684-10.2011
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发表时间：
2011-06-15
期刊：
影响因子：
--
通讯作者：
Gershon MD
中科院分区：
文献类型：
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作者：
Li Z;Chalazonitis A;Huang YY;Mann JJ;Margolis KG;Yang QM;Kim DO;Côté F;Mallet J;Gershon MD
肠道中的肠嗜铬细胞（EC）中含有一个大的5-HT库，而肠神经系统（ENS）中含有一个较小的5-HT库。在发育过程中，肠神经元异步产生。我们检验了以下假设：早期出现的多巴胺能神经元影响晚出生的多巴胺能、GABA能、氮能和降钙素基因相关肽表达神经元的发育/存活，并且对胃肠动力至关重要。5-HT的生物合成依赖于EC细胞中的色氨酸羟化酶1（TPH 1）和神经元中的TPH 2;因此，缺乏TPH 1和/或TPH 2的小鼠可以区分EC来源的5-HT和神经元来源的5-HT。TPH 2的缺失，而不是TPH 1，降低肌间神经元密度和多巴胺能和GABA能神经元的比例，但不影响肠道的外源性交感神经支配;在缺乏TPH 2的小鼠中，肠道传输减慢，但胃排空加速。分离的肠嵴来源细胞（ENCDC）表达5-羟色胺再摄取转运体（SERT）和15种5-HT受体亚型。此外，5-羟色胺的孤立ENCDC的文化促进总和多巴胺能神经元的发展。SERT免疫反应性终末轴突环包围肌间多巴胺能神经元和SERT敲除增加肠多巴胺代谢产物的水平，这意味着肠多巴胺能神经元接受多巴胺能神经支配。观察结果表明，组成性胃肠动力更多地依赖于神经元比EC细胞血清素;此外，多巴胺能神经元促进发育/存活的一些类的晚出生的肠神经元，包括多巴胺能神经元，这似乎在成人ENS神经支配和激活。
The gut contains a large 5-HT pool in enterochromaffin (EC) cells and a smaller 5-HT pool in the enteric nervous system (ENS). During development, enteric neurons are generated asynchronously. We tested hypotheses that serotonergic neurons, which arise early, affect development/survival of later-born dopaminergic, GABAergic, nitrergic, and calcitonin gene-related peptide-expressing neurons and are essential for gastrointestinal motility. 5-HT biosynthesis depends on tryptophan hydroxylase 1 (TPH1) in EC cells and on TPH2 in neurons; therefore, mice lacking TPH1 and/or TPH2 distinguish EC-derived from neuronal 5-HT. Deletion of TPH2, but not TPH1, decreased myenteric neuronal density and proportions of dopaminergic and GABAergic neurons but did not affect the extrinsic sympathetic innervation of the gut; intestinal transit slowed in mice lacking TPH2 mice, but gastric emptying accelerated. Isolated enteric crest-derived cells (ENCDCs) expressed the serotonin reuptake transporter (SERT) and 15 subtypes of 5-HT receptor. Addition of 5- HT to cultures of isolated ENCDCs promoted total and dopaminergic neuronal development. Rings of SERT-immunoreactive terminal axons surrounded myenteric dopaminergic neurons and SERT knock-out increased intestinal levels of dopamine metabolites, implying that enteric dopaminergic neurons receive a serotonergic innervation. Observations suggest that constitutive gastrointestinal motility depends more on neuronal than EC cell serotonin; moreover, serotonergic neurons promote development/survival of some classes of late-born enteric neurons, including dopaminergic neurons, which appear to innervate and activate in the adult ENS.