TY - JOUR
T1 - Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons
AU - Li, Zhishan
AU - Chalazonitis, Alcmène
AU - Huang, Yung Yu
AU - Mann, J. John
AU - Margolis, Kara Gross
AU - Yang, Qi Melissa
AU - Kim, Dolly O.
AU - Côté, Francine
AU - Mallet, Jacques
AU - Gershon, Michael D.
PY - 2011/6/15
Y1 - 2011/6/15
N2 - 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.
AB - 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.
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U2 - 10.1523/JNEUROSCI.6684-10.2011
DO - 10.1523/JNEUROSCI.6684-10.2011
M3 - Article
C2 - 21677183
AN - SCOPUS:79959285660
SN - 0270-6474
VL - 31
SP - 8998
EP - 9009
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 24
ER -