Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons
Open accessAbstract
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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The neuronal pool of 5-HT, rather than the majority EC-cell pool, is most critical for ENS development and motility.
“Although the vast majority of intestinal 5-HT is located in the EC cells, it is the neuronal pool of 5-HT that is most critical for ENS development and motility [26, 27].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [27]
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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
- Publisher
- Society for Neuroscience
- Published
- 2011-06-15
- Volume
- 31
- Issue
- 24
- Pages
- 8998-9009
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4442094
- 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
- bronze
- doi.org
- 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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