Effect of Maternal Dietary DHA and Prenatal Stress Mouse Model on Autistic-like Behaviors, Lipid Peroxidation Activity, and GABA Expression in Offspring Pups

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted social communication and repetitive behaviors. Prenatal stress is critical in neurodevelopment and increases risk for ASD, particularly in those with greater genetic susceptibility to stress. Docosahexaenoic acid (DHA) is one of the most abundant ω-3 fatty acids in the membrane phospholipids of the mammalian brain, and dietary DHA plays an important role in brain development and maintenance of brain structure. In this study, we investigated whether peri-natal supplementation of DHA can alleviate autistic-like behaviors in a genetic risk/stress mouse model and how it alters lipid peroxidation activity and GABAergic system gene expression in the forebrain. Pregnant heterozygous serotonin transporter knockout (SERT-KO) and wild-type (WT) dams were placed in either non-stressed control conditions or chronic variable stress (CVS) conditions and fed either a control diet or a DHA-rich (1% by weight) diet. Offspring of each group were assessed for anxiety and autism-associated behavior at post-natal day 60 using an open field test, elevated plus maze test, repetitive behavior, and the 3-chamber social approach test. A liquid chromatography-mass spectrometry (LC-MS)-based method was used to follow changes in levels of lipid peroxidation products in the cerebral cortex. Male offspring of prenatally stressed SERT-het KO dams exhibited decreased social preference behaviors and increased repetitive grooming behaviors compared to WT control offspring. Moreover, DHA supplementation in male SERT-het mice decreased frequency of grooming behaviors albeit showing no associated effects on social behaviors. Regardless of stress conditions, supplementation of DHA to the WT mice did not result in alterations in grooming nor social interaction in the offspring. Furthermore, no apparent changes were observed in the lipid peroxidation products comparing the stressed and non-stressed brains. <i>Gad2</i> was downregulated in the cortex of female offspring of prenatally stressed SERT-KO dams, and this change appeared to be rescued by DHA supplementation in offspring. <i>Gad2</i> was upregulated in the striatum of male offspring of prenatally stressed SERT-KO dams, but DHA did not significantly alter the expression compared to the control diet condition.