The DOI matches its Crossref record; 75 of the 77 references it cites were found in a registry or an index.
Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function
Open accessAbstract
Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation.
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“Murine models possessing abnormalities in SERT during development, such as SERT knockout mice, as well as mice that receive selective serotonin reuptake inhibitors during pregnancy and breastfeeding, exhibit ENS hyperplasia as well as long-lasting deficits in ENS-mediated functions, including in vivo and in vitro gastrointestinal motility [33].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [33]
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“both of which may be contributory to the demonstrated increase in whole blood 5-HT levels [33].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [33]
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“As a consequence of abnormal ENS development, SERT Ala56 mice have abnormally slowed in vivo and in vitro motility throughout the entire intestine, including a decrease in the frequency and speed of colonic peristaltic contractions”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [33]
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Cites
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Self-citationGastrointestinal Symptoms in Autism Spectrum Disorder: A Meta-analysis
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Self-citationA transient placental source of serotonin for the fetal forebrain
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The microbiota-gut-brain axis: from motility to mood
Margolis, K. G., Cryan, J. F., & Mayer, E. A. (2021) · Gastroenterology · doi:10.1053/j.gastro.2020.10.066 · Cited by 999
The bowel and beyond: The enteric nervous system in neurological disorders
Rao, M., & Gershon, M. D. (2016) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.107 · Cited by 629
Self-citationSharkey, K. A., & Mawe, G. M. (2022) · Physiological Reviews · doi:10.1152/physrev.00018.2022 · Cited by 447
Luna, R. A., Oezguen, N., Balderas, M., Venkatachalam, A., Runge, J. K., Versalovic, J., Veenstra-VanderWeele, J., Anderson, G. M., Savidge, T., & Williams, K. C. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2016.11.008 · Cited by 295
“Furthermore, a recent study showed that an ASD-associated serotonin transporter variant leads to altered gut development and function.(64) Our microbial correlations provide further evidence for the relevance of the tryptophan–serotonin pathway in ASD,(62) although our sample size did not allow us to focus on an ASD s…”
BackgroundSelf-citationNon-conventional features of peripheral serotonin signalling — the gut and beyond
Spohn, S. N., & Mawe, G. M. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.51 · Cited by 282
Metadata
- Authors
- Margolis, K. G., Li, Z., Stevanovic, K., Saurman, V., Israelyan, N., Anderson, G. M., Snyder, I., Veenstra-VanderWeele, J., Blakely, R. D., & Gershon, M. D.
- Affiliations
- Columbia University (US)
- Yale University (US)
- Vanderbilt University (US)
- Corresponding author
- Margolis, Kara Gross
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-04-25
- Volume
- 126
- Issue
- 6
- Pages
- 2221-2235
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4887174
- OpenAlex
- W2343547480
- Cited by
- 139
- References
- 77
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 12 · 2023: 23 · 2022: 17 · 2021: 15 · 2020: 16 · 2019: 17 · 2018: 10 · 2017: 11 · 2016: 4
- FWCI
- 8.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Autism Research Institute (NS15547, DK093786)
- National Institutes of Health (5r01ns015547-39, NS15547, MH096972)
- National Institute of Mental Health (P50MH096972, R01MH094604)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK093786)
- National Institute of Neurological Disorders and Stroke (R01-NS015547)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- autism spectrum disorder, serotonin transporter, gastrointestinal dysfunction, fluoxetine, 5-HT4 receptor agonist, peristalsis, gut-brain axis, mouse model
- MeSH terms
- Autism Spectrum Disorder, Animals, Female, Gastrointestinal Motility, Humans, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Pregnancy, Serotonin, Genetic Variation, Enteric Nervous System, Mice, Knockout, Models, Animal, Gastrointestinal Tract, Serotonin Plasma Membrane Transport Proteins, Mice, Neurogenesis, Mice, 129 Strain
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