Serotonin Transporter Function and Prenatal Stress Interact to Modulate Sociability in Mice

Background: Multiple studies have reported that prenatal stress is a possible risk factor for the development of autism spectrum disorder (ASD). In rodents, adult rats exposed to prenatal stress display a significant reduction in sociability, a diagnostic hallmark for ASD in humans. Genes that contribute to stress reactivity may, therefore, exacerbate prenatal stress-mediated behavioral changes in the adult offspring. Humans with the short allele of an insertion/deletion polymorphism of the SLC6A4 gene, which reduces the expression and function of the serotonin transporter (SERT), display increased stress reactivity. Some studies also link this gene locus and specific polymorphism to ASD. Heterozygous SERT knockout mice (SERT +/-) show reductions in SERT function and expression similar to the human short polymorphism.

Objectives: We wished to examine the role of SERT function and prenatal stress in mice, in order to determine whether they interact to produce reductions in social behavior in the adult offspring.

Methods: We subjected pregnant SERT +/- dams to chronic variable stress and subsequently tested the adult offspring for sociability using a 3-chamber social approach task (Nadler et al., 2004).

Results: Offspring male SERT +/- mice exposed to prenatal stress displayed reduced social novelty-seeking behavior, as they spent significantly less time socially interacting with a novel versus familiar mouse. Wild-type and unstressed SERT +/- male mice displayed typical social novelty-seeking behavior.

Conclusions: Our findings indicate that prenatal stress may interact with reduced SERT function to produce changes in sociability consistent with those observed in ASD. Given previous research implicating the SERT gene locus and prenatal stress as possible risk factors for ASD, our findings provide evidence for a possible interaction between these environmental and genetic factors that contribute to the production of autistic-like behavior in mice.