Cited by 403Gastrointestinal motility and disordersCongenital gastrointestinal and neural anomaliesNeuropeptides and Animal Physiology

Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons

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Li, Z., Chalazonitis, A., Huang, Y.-y., Mann, J. J., Margolis, K. G., Yang, Q. M., Kim, D. O., Cote, F. +2 more·2011·Journal of Neuroscience

Abstract

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.

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Authors
Li, Z., Chalazonitis, A., Huang, Y.-Y., Mann, J. J., Margolis, K. G., Yang, Q. M., Kim, D. O., Cote, F., Mallet, J., & Gershon, M. D.
Affiliations
  • Columbia University Irving Medical Center (US)
  • Columbia University (US)
  • Lexicon Pharmaceuticals (United States) (US)
  • Centre National de la Recherche Scientifique (FR)
Venue
Journal of Neuroscience
Published
2011-06-15
Volume
31
Issue
24
Pages
8998-9009
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2168678503
Cited by
403
References
76
Citations by year
2026: 8 · 2025: 26 · 2024: 26 · 2023: 23 · 2022: 34 · 2021: 40 · 2020: 37 · 2019: 31 · 2018: 41 · 2017: 16 · 2016: 30 · 2015: 29 · 2014: 15 · 2013: 24 · 2012: 20
FWCI
20.35
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • National Institutes of Health (5r01ns015547-39)
  • National Institute of Neurological Disorders and Stroke (R01NS012969, NS12969, R01-NS015547, NS 15547)
Topics
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
enteric nervous system, enterochromaffin cells, tryptophan hydroxylase 1, tryptophan hydroxylase 2, neuronal development, gastrointestinal motility, serotonin transporter, serotonin receptors, myenteric neurons, GABAergic neurons, nitrergic neurons, intestinal transit, gastric emptying
MeSH terms
ELAV-Like Protein 3, Animals, Dopamine, Embryo, Mammalian, Enzyme Inhibitors, gamma-Aminobutyric Acid, Gastric Emptying, Gastrointestinal Motility, Homovanillic Acid, Intestine, Small, Mice, Inbred C57BL, Myenteric Plexus, Neurons, Serotonin, Tryptophan Hydroxylase, Tyrosine 3-Monooxygenase, Calcitonin Gene-Related Peptide, Enteric Nervous System, Gene Expression Regulation, Developmental, Serotonin Plasma Membrane Transport Proteins, Mice, ELAV Proteins, Nitric Oxide Synthase Type I, In Vitro Techniques

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