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Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function
Kara Gross Margolis, … , Randy D. Blakely, Michael D. Gershon
Kara Gross Margolis, … , Randy D. Blakely, Michael D. Gershon
Published April 25, 2016
Citation Information: J Clin Invest. 2016;126(6):2221-2235. https://doi.org/10.1172/JCI84877.
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Research Article Gastroenterology

Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function

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Abstract

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.

Authors

Kara Gross Margolis, Zhishan Li, Korey Stevanovic, Virginia Saurman, Narek Israelyan, George M. Anderson, Isaac Snyder, Jeremy Veenstra-VanderWeele, Randy D. Blakely, Michael D. Gershon

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Figure 1

Numbers of total and late-born enteric neurons are lower in SERT Ala56 than in WT mice.

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Numbers of total and late-born enteric neurons are lower in SERT Ala56 t...
n = 6–7/group. (A–D) Submucosal plexus, small intestine: (A) Total neurons. (B) Dopaminergic neurons (TH-immunoreactive). (C) CGRP-immunoreactive neurons. (D) Dopaminergic and CGRP-expressing neurons as a proportion of total neurons. (E–H) Myenteric plexus: (E) Total neurons, small intestine. (F) Total neurons, colon. (G) GABAergic neurons, small intestine. (H) GABAergic neurons, colon. (I and J) Submucosal HuC/D-immunoreactive neurons (blue): I shows WT; J shows SERT Ala56. (K and L) Submucosal TH-immunoreactive neurons (red): K shows WT; L shows SERT Ala56. (M and N) Submucosal CGRP-immunoreactive neurons (green): M shows WT; N shows SERT Ala56. (O and P) Myenteric HuC/D-immunoreactive neurons, small intestine (green): O shows WT; P shows SERT Ala56. (Q and R) Myenteric HuC/D-immunoreactive neurons, colon (green): Q shows WT; R shows SERT Ala56. (S and T) Myenteric GABA-immunoreactive neurons, small intestine (blue): S shows WT; T shows SERT Ala56. (U and V) Myenteric GABA-immunoreactive neurons, colon (blue): U shows WT; V shows SERT Ala56. Scale bars in N (applies to I–N), R (applies to O–R), and V (applies to S–V): 30 μm. Hu-C/D, pan-neuronal marker.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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