Combined effect of maternal serotonin transporter genotype and prenatal stress in modulating offspring social interaction in mice

Abstract

Several studies suggest that prenatal stress is a possible risk factor in the development of autism spectrum disorders. However, many children exposed to stress prenatally are born healthy and develop typically, suggesting that other factors must contribute to autism. Genes that contribute to stress reactivity may, therefore, exacerbate prenatal stress-mediated behavioral changes in the adult offspring. One candidate gene linked to increased stress reactivity encodes the serotonin transporter. Specifically, an insertion/deletion (long/short allele) polymorphism upstream of the serotonin transporter gene correlates with differential expression and function of the serotonin transporter and a heightened response to stressors. Heterozygous serotonin transporter knockout mice show reductions in serotonin transporter expression similar to the human short polymorphism. In this study, the role of prenatal stress and maternal serotonin transporter genotype were assessed in mice to determine whether their combined effect produces reductions in social behavior in the adult offspring. Pregnant serotonin transporter heterozygous knockout and wild-type dams were placed in either a control condition or subjected to chronic variable stress. The adult offspring were subsequently assessed for social interaction and anxiety using a 3-chamber social approach task, ultrasonic vocalization detection, elevated-plus maze and an open field task. Results indicated that prenatal stress and reduced serotonin transporter expression of the dam may have the combined effect of producing changes in social interaction and social interest in the offspring consistent with those observed in autism spectrum disorder. This data indicates a possible combined effect of maternal serotonin transporter genotype and prenatal stress contributing to the production of autistic-like behaviors in offspring.

Disruption of adult expression of sexually selected traits by developmental exposure to bisphenol A

“…On postnatal day 25, offspring were assessed to ensure that neuromuscular, sensory, and other functional systems were intact, as described previously (60,61). Olfaction was tested by placing a small piece of food (cookie crumbs, 20 mg) under the bedding in a clean mouse cage that was visually, but not physically, divided into nine quadrants.…”

Genetic and pharmacological manipulations of the serotonergic system in early life: neurodevelopmental underpinnings of autism-related behavior

“…Furthermore, in line with the repetitive behaviors displayed by ASD patients (Pierce and Courchesne, 2001), 5-HTT knockout mice displayed higher frequencies of self-grooming than their wild-type littermates (Kalueff et al, 2010; Lewejohann et al, 2010). In the domain of communication, which is affected in ASD, it has been reported that wild-type mice show more ultrasonic vocalizations (USVs) within the 20–40 kHz range than prenatally stressed animals of both 5-HTT +/+ and 5-HTT +/− genotypes, as well as non-stressed 5-HTT +/− animals (Jones et al, 2010). Furthermore, 5-HTT −/− rats show reduced prepulse inhibition (Page et al, 2009), implying the sensorimotor integration is impaired in these animals, such that they are unable to efficiently select sensory information from the external world.…”

Phenotyping, Etiological Factors, and Biomarkers: Toward Precision Medicine in Autism Spectrum Disorders

“…132 The risk of ASD associated with prenatal psychosocial stress seems to be linked to maternal genetic susceptibility to greater stress reactivity. 133 Furthermore, in a rodent model, prenatal stress exposure in offspring of genetically stress susceptible mothers has been shown to result in aberrant social behavior, 134 which was also associated with delayed migration of GABAergic neurons during development. 135 Maternal exposure to stress before pregnancy and even early life stress is associated with increased risk for development of ASD in subsequent pregnancies according to recent findings in data from the Nurses' Health Study.…”

“…For example, patients who do not have a known ASD-associated GABAergic mutation but who have a similar level of GABAergic activity, as potentially assessed by magnetic resonance spectroscopy or electroencephalography markers, 57,63 as patients with these mutations might also be expected to respond similarly to drugs developed based on the GABAergic mutation-based ASD mouse model. Furthermore, animal models have also been developed for environmental factors, including prenatal stress models, 134 maternal immune models, 125,126,177 and drug effect models. 148 Therefore, these principles can also be extended to incorporate environmental cause/risk factors onto the cause/biomarker map of developing neural systems.…”