Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function Article Swipe
Kara Gross Margolis
,
Zhishan Li
,
Korey D. Stevanovic
,
Virginia Saurman
,
Narek Israelyan
,
George M. Anderson
,
Isaac Snyder
,
Jeremy Veenstra‐VanderWeele
,
Randy Blakely
,
Michael D. Gershon
·
YOU?
·
· 2016
· Open Access
·
· DOI: https://doi.org/10.1172/jci84877
YOU?
·
· 2016
· Open Access
·
· DOI: https://doi.org/10.1172/jci84877
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.
Related Topics
Concepts
Serotonin Plasma Membrane Transport Proteins
Serotonin transporter
Serotonin
Biology
Endocrinology
Serotonin Uptake Inhibitors
Internal medicine
Phenotype
Neurogenesis
Neuroscience
Medicine
Fluoxetine
Receptor
Gene
Biochemistry
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1172/jci84877
- http://www.jci.org/articles/view/84877/files/pdf
- OA Status
- bronze
- Cited By
- 136
- References
- 79
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W2343547480
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W2343547480Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1172/jci84877Digital Object Identifier
- Title
-
Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and functionWork title
- Type
-
articleOpenAlex work type
- Language
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enPrimary language
- Publication year
-
2016Year of publication
- Publication date
-
2016-04-24Full publication date if available
- Authors
-
Kara Gross Margolis, Zhishan Li, Korey D. Stevanovic, Virginia Saurman, Narek Israelyan, George M. Anderson, Isaac Snyder, Jeremy Veenstra‐VanderWeele, Randy Blakely, Michael D. GershonList of authors in order
- Landing page
-
https://doi.org/10.1172/jci84877Publisher landing page
- PDF URL
-
https://www.jci.org/articles/view/84877/files/pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
bronzeOpen access status per OpenAlex
- OA URL
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https://www.jci.org/articles/view/84877/files/pdfDirect OA link when available
- Concepts
-
Serotonin Plasma Membrane Transport Proteins, Serotonin transporter, Serotonin, Biology, Endocrinology, Serotonin Uptake Inhibitors, Internal medicine, Phenotype, Neurogenesis, Neuroscience, Medicine, Fluoxetine, Receptor, Gene, BiochemistryTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
136Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 8, 2024: 12, 2023: 24, 2022: 20, 2021: 15Per-year citation counts (last 5 years)
- References (count)
-
79Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.slow | 91 |
| abstract_inverted_index.that | 10, 69, 75, 126, 137, 169, 180 |
| abstract_inverted_index.when | 146 |
| abstract_inverted_index.with | 13 |
| abstract_inverted_index.(ASD) | 3 |
| abstract_inverted_index.5-HT. | 83 |
| abstract_inverted_index.5-HT4 | 157 |
| abstract_inverted_index.Ala56 | 160 |
| abstract_inverted_index.Here, | 66 |
| abstract_inverted_index.These | 84 |
| abstract_inverted_index.cause | 148 |
| abstract_inverted_index.crypt | 101 |
| abstract_inverted_index.given | 118 |
| abstract_inverted_index.leads | 173 |
| abstract_inverted_index.those | 77 |
| abstract_inverted_index.(5-HT) | 38 |
| abstract_inverted_index.(SERT, | 40 |
| abstract_inverted_index.Autism | 0 |
| abstract_inverted_index.causes | 63 |
| abstract_inverted_index.cells. | 103 |
| abstract_inverted_index.clear, | 20 |
| abstract_inverted_index.coding | 33 |
| abstract_inverted_index.common | 7, 53 |
| abstract_inverted_index.during | 162, 184, 201 |
| abstract_inverted_index.reflex | 96 |
| abstract_inverted_index.system | 89 |
| abstract_inverted_index.(Ala56) | 56 |
| abstract_inverted_index.SLC6A4) | 43 |
| abstract_inverted_index.agonist | 158 |
| abstract_inverted_index.defects | 74, 85 |
| abstract_inverted_index.display | 72 |
| abstract_inverted_index.encoded | 41 |
| abstract_inverted_index.enteric | 87, 141 |
| abstract_inverted_index.further | 204 |
| abstract_inverted_index.lacking | 81 |
| abstract_inverted_index.nervous | 88 |
| abstract_inverted_index.progeny | 114 |
| abstract_inverted_index.propose | 179 |
| abstract_inverted_index.relates | 25 |
| abstract_inverted_index.support | 134 |
| abstract_inverted_index.variant | 55 |
| abstract_inverted_index.warrant | 203 |
| abstract_inverted_index.ASD-like | 64 |
| abstract_inverted_index.activity | 133, 172 |
| abstract_inverted_index.disorder | 2 |
| abstract_inverted_index.features | 192 |
| abstract_inverted_index.however, | 21 |
| abstract_inverted_index.included | 86 |
| abstract_inverted_index.neuronal | 82, 142 |
| abstract_inverted_index.opposite | 105 |
| abstract_inverted_index.presents | 12 |
| abstract_inverted_index.resemble | 76 |
| abstract_inverted_index.resulted | 127 |
| abstract_inverted_index.spectrum | 1 |
| abstract_inverted_index.transit, | 93 |
| abstract_inverted_index.variants | 34 |
| abstract_inverted_index.Multiple, | 30 |
| abstract_inverted_index.activity, | 97 |
| abstract_inverted_index.clearance | 61 |
| abstract_inverted_index.condition | 9 |
| abstract_inverted_index.decreased | 131 |
| abstract_inverted_index.deficient | 181 |
| abstract_inverted_index.excessive | 170 |
| abstract_inverted_index.features. | 29 |
| abstract_inverted_index.function. | 153 |
| abstract_inverted_index.increased | 129 |
| abstract_inverted_index.increases | 59 |
| abstract_inverted_index.phenotype | 106 |
| abstract_inverted_index.pregnancy | 202 |
| abstract_inverted_index.prevented | 164 |
| abstract_inverted_index.regulates | 140 |
| abstract_inverted_index.serotonin | 37 |
| abstract_inverted_index.signaling | 139, 183 |
| abstract_inverted_index.targeting | 199 |
| abstract_inverted_index.therapies | 198 |
| abstract_inverted_index.Expression | 49 |
| abstract_inverted_index.antagonist | 121 |
| abstract_inverted_index.behavioral | 8, 191 |
| abstract_inverted_index.behaviors. | 65 |
| abstract_inverted_index.contribute | 187 |
| abstract_inverted_index.diminished | 94 |
| abstract_inverted_index.disturbed, | 147 |
| abstract_inverted_index.epithelial | 102 |
| abstract_inverted_index.frequently | 11 |
| abstract_inverted_index.identified | 46 |
| abstract_inverted_index.inadequate | 175 |
| abstract_inverted_index.phenotypes | 125 |
| abstract_inverted_index.reciprocal | 124 |
| abstract_inverted_index.suggesting | 168 |
| abstract_inverted_index.development | 143, 163, 185 |
| abstract_inverted_index.dysfunction | 24 |
| abstract_inverted_index.evaluation. | 205 |
| abstract_inverted_index.fluoxetine. | 122 |
| abstract_inverted_index.hypoplasia, | 90 |
| abstract_inverted_index.peristaltic | 95 |
| abstract_inverted_index.transporter | 39 |
| abstract_inverted_index.consequences | 196 |
| abstract_inverted_index.demonstrated | 68 |
| abstract_inverted_index.increasingly | 6 |
| abstract_inverted_index.long-lasting | 149 |
| abstract_inverted_index.abnormalities | 150 |
| abstract_inverted_index.disturbances. | 16 |
| abstract_inverted_index.neurogenesis. | 177 |
| abstract_inverted_index.proliferation | 99 |
| abstract_inverted_index.5-HT4-mediated | 176 |
| abstract_inverted_index.Administration | 154 |
| abstract_inverted_index.SERT-deficient | 110 |
| abstract_inverted_index.perturbations, | 167 |
| abstract_inverted_index.hyperfunctional | 32 |
| abstract_inverted_index.Ala56-associated | 165 |
| abstract_inverted_index.Ala56-expressing | 70 |
| abstract_inverted_index.gastrointestinal | 14 |
| cited_by_percentile_year.max | 100 |
| cited_by_percentile_year.min | 97 |
| corresponding_author_ids | https://openalex.org/A5040278204 |
| countries_distinct_count | 1 |
| institutions_distinct_count | 10 |
| corresponding_institution_ids | https://openalex.org/I4210147155 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.8600000143051147 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.98644604 |
| citation_normalized_percentile.is_in_top_1_percent | True |
| citation_normalized_percentile.is_in_top_10_percent | True |