A balanced omega-6/omega-3 polyunsaturated fatty acid diet suffices to prevent autism spectrum disorder symptoms in an environmental mouse model

Abstract Exploration of potential nutritional therapies in autism spectrum disorder (ASD), notably through omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation, have been explored but remain elusive as to their specific contribution to the phenotype and their potential in ameliorating cardinal symptoms of the disease. Here, we compared the effects of two diets that differ in their n-3 PUFA species on ASD symptoms in the valproic acid (VPA) mouse model. For this, pregnant C57BL/6J females were i.p. injected with VPA at embryonic day 12.5 (E12.5; 450mg/kg) and fed with either a balanced diet (n-3 bal) with alpha-linolenic acid (ALA) as the only n-3 PUFA source or a n-3 long-chain PUFA (LCPUFA) supplemented diet (n-3 supp) with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) as the major n-3 PUFA species. Diets were provided starting E0, throughout lactation and on to the offspring after weaning through adulthood. Maternal and pup behaviors were investigated followed by social, motor and gait behavior in young adult offspring. Post-mortem investigations included cerebellar Purkinje cell (PC) count, liver and cerebellar fatty acid (FA) composition, inflammation markers’ levels and microbiota composition. All experiments were performed separately on male and female offspring. Developmental milestones were delayed in the n-3 LCPUFA groups, whatever the treatment. VPA-exposed offspring did not show social deficits, stereotypies, or PC loss. Global activity and gait were altered by diet and treatment with sex differences. TNF-alpha cerebellar levels were slightly increased by n-3 LCPUFA supplementation, only in females. With both diets, VPA did not alter microbiota composition in male and female offspring nor cerebellar n-3 LCPUFA levels, except in females. Our results indicate that a balanced n-3/n-6 PUFA diet may suffice to protect from ASD symptoms and physiopathology, and that n-3 LCPUFA supplementation brings limited benefits in the VPA mouse model.