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

Zhishan Li, Alcmène Chalazonitis, Yung Yu Huang, J. John Mann, Kara Gross Margolis, Qi Melissa Yang, Dolly O. Kim, Francine Côté, Jacques Mallet, Michael D. Gershon

Research output: Contribution to journalArticlepeer-review

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/survivaloflater-borndopaminergic,GABAergic, nitrergic,and calcitoningene-relatedpeptide-expressingneuronsandare 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) expressedthe serotonin reuptaketransporter (SERT)and15subtypesof5-HTreceptor. Additionof5-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.

Original languageEnglish (US)
Pages (from-to)8998-9009
Number of pages12
JournalJournal of Neuroscience
Volume31
Issue number24
DOIs
StatePublished - Jun 15 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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