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Molecular Autism
Published in: Molecular Autism 1/2013

Open Access 01-12-2013 | Research

Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice

Authors: Travis M Kerr, Christopher L Muller, Mahfuzur Miah, Christopher S Jetter, Rita Pfeiffer, Charisma Shah, Nicole Baganz, George M Anderson, Jacqueline N Crawley, James S Sutcliffe, Randy D Blakely, Jeremy Veenstra-VanderWeele

Published in: Molecular Autism | Issue 1/2013

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Abstract

Background

Previously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes.

Methods

To explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity.

Results

One consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior.

Conclusions

Our findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans.
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Metadata
Title
Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice
Authors
Travis M Kerr
Christopher L Muller
Mahfuzur Miah
Christopher S Jetter
Rita Pfeiffer
Charisma Shah
Nicole Baganz
George M Anderson
Jacqueline N Crawley
James S Sutcliffe
Randy D Blakely
Jeremy Veenstra-VanderWeele
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2013
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/2040-2392-4-35

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