Interplay between maternal Slc6a4 mutation and prenatal stress: a possible mechanism for autistic behavior development.

The low activity allele of the maternal polymorphism, 5HTTLPR, in the serotonin transporter, SLC6A4, coupled with prenatal stress is reported to increase the risk for children to develop autism spectrum disorder (ASD). Similarly, maternal Slc6a4 knock-out and prenatal stress in rodents results in offspring demonstrating ASD-like characteristics. The present study uses an integrative genomics approach to explore mechanistic changes in early brain development in mouse embryos exposed to this maternal gene-environment phenomenon. Restraint stress was applied to pregnant Slc6a4 +/+ and Slc6a4 +/- mice and post-stress embryonic brains were assessed for whole genome level profiling of methylome, transcriptome and miRNA using Next Generation Sequencing. Embryos of stressed Slc6a4 +/+ dams exhibited significantly altered methylation profiles and differential expression of 157 miRNAs and 1009 genes affecting neuron development and cellular adhesion pathways, which may function as a coping mechanism to prenatal stress. In striking contrast, the response of embryos of stressed Slc6a4 +/- dams was found to be attenuated, shown by significantly reduced numbers of differentially expressed genes (458) and miRNA (0) and genome hypermethylation. This attenuated response may pose increased risks on typical brain development resulting in development of ASD-like characteristics in offspring of mothers with deficits in serotonin related pathways during stressful pregnancies.

Maternal diet rich in omega-6 polyunsaturated fatty acids during gestation and lactation produces autistic-like sociability deficits in adult offspring.

Multiple studies have reported prenatal stress as a potential risk factor for the development of autism spectrum disorder (ASD). In rodents, a significant reduction in sociability is seen in prenatally stressed offspring of genetically stress-susceptible dams. Certain dietary factors that contribute to stress reactivity may, therefore, exacerbate prenatal stress-mediated behavioral changes in adult offspring. Adults with a diet rich in omega-6 polyunsaturated fatty acids (PUFAs) display increased stress reactivity. In the current study, the effects of prenatal diet and prenatal stress on social behavior in adult offspring mice were examined. Pregnant C57BL/6J dams received either chronic variable stress or no stress, and were also placed on a control diet or a diet rich in omega-6 PUFAs, in a 2×2 design. We subsequently tested the adult offspring for sociability, anxiety, and locomotor behaviors using a 3-chambered social approach task, an elevated-plus maze, an open field task and a rotarod task. Results indicated that a maternal diet rich in omega-6 PUFAs during gestation and lactation produce changes in sociability consistent with those observed in ASD. Additionally, offspring exposed to a diet rich in omega-6 PUFAs during gestation and lactation had increased levels of anxiety in the elevated-plus maze. Prenatal stress had no effect on offspring behavior. These findings provide evidence for a possible environmental risk factor that contributes to the production of autistic-like behavior in mice.