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

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 7

Prucalopride treatment during development rescues SERT Ala56 mice from ENS hypoplasia and associated abnormalities of GI motility.

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Prucalopride treatment during development rescues SERT Ala56 mice from E...
Treatment with prucalopride during development rescued SERT Ala56 mice from ENS hypoplasia (n = 3–4/group) and associated abnormalities of GI motility (n = 14–36/group for in vivo motility studies, 2 trials; 3–4/group for peristalsis). (A–C) Submucosal plexus. (A) Total neurons. Fewer neurons were found in SERT Ala56 than in WT mice. Prucalopride did not affect the number of neurons in WT animals but eliminated hypoplasia in SERT Ala56 mice. (B) TH-immunoreactive neurons. Prucalopride prevented the deficiency in SERT Ala56 mice. (C) CGRP-immunoreactive neurons. Prucalopride prevented the deficiency in SERT Ala56 mice. (D and E) Myenteric plexus. Total neurons (D) and GABAergic neurons (E) were fewer in SERT Ala56 mice than in WT mice. Numbers of total and GABAergic neurons were normalized by prucalopride administration to SERT Ala56 mice. (F) Total GIT was longer in SERT Ala56 mice than in WT mice. Prucalopride eliminated slow transit in SERT Ala56 mice but did not affect total GIT when given similarly to WT mice. (G) Colonic motility was significantly longer in SERT Ala56 than in WT mice. Prucaloparide eliminated this defect in SERT Ala56 animals but did not significantly affect colonic motility when given to WT mice. (H–J) CMMCs in isolated colon. Frequency (H), velocity (I), and conduction length (J) were all lower in SERT Ala56 mice than in WT mice. Prucalopride eliminated each of these defects when given to SERT Ala56 mice but did not significantly alter CMMC parameters when given to WT animals. Student’s unpaired t test and 1-way ANOVA were used, respectively, to compare single and multiple means. For the box-and-whisker plot, the boxes represent the first and third quartiles, the whiskers are 95% confidence interval, and the lines within the boxes are median values.