Autism spectrum disorders (ASD) are complex conditions that stem from a combination of genetic, epigenetic and environmental influences during early pre- and postnatal childhood. The review focuses on the cerebellum and the striatum, two structures involved in motor, sensory, cognitive and social functions altered in ASD. We summarize clinical and fundamental studies highlighting the importance of these two structures in ASD. We further discuss the relation between cellular and molecular alterations with the observed behavior at the social, cognitive, motor and gait levels. Functional correlates regarding neuronal activity are also detailed wherever possible, and sexual dimorphism is explored pointing to the need to apprehend ASD in both sexes, as findings can be dramatically different at both quantitative and qualitative levels. The review focuses also on a set of three recent papers from our laboratory where we explored motor and gait function in various genetic and environmental ASD animal models. We report that motor and gait behaviors can constitute an early and quantitative window to the disease, as they often correlate with the severity of social impairments and loss of cerebellar Purkinje cells. The review ends with suggestions as to the main obstacles that need to be surpassed before an appropriate management of the disease can be proposed.
Dietary supplementations with n-3 polyunsaturated fatty acid (PUFA) have been explored in autism spectrum disorder (ASD) but their efficiency and potential in ameliorating cardinal symptoms of the disease remain elusive. Here, we compared a n-3 long-chain (LC) PUFA dietary supplementation (n-3 supp) obtained from fatty fish with a n-3 PUFA precursor diet (n-3 bal) obtained from plant oils in the valproic acid (VPA, 450 mg/kg at E12.5) ASD mouse model starting from embryonic life, throughout lactation and until adulthood. Maternal and offspring behaviors were investigated as well as several VPA-induced ASD biological features: cerebellar Purkinje cell (PC) number, inflammatory markers, gut microbiota, and peripheral and brain PUFA composition. Developmental milestones were delayed in the n-3 supp group compared to the n-3 bal group in both sexes. Whatever the diet, VPA-exposed offspring did not show ASD characteristic alterations in social behavior, stereotypies, PC number, or gut microbiota dysbiosis while global activity, gait, peripheral and brain PUFA levels as well as cerebellar TNF-alpha levels were differentially altered by diet and treatment according to sex. The current study provides evidence of beneficial effects of n-3 PUFA based diets, including one without LCPUFAs, on preventing several behavioral and cellular symptoms related to ASD.
Autism spectrum disorders (ASDs) are defined as a set of neurodevelopmental disorders and a lifelong condition. In mice, most of the studies focused on the developmental aspects of these diseases. In this paper, we examined the evolution of motor stereotypies through adulthood in the Shank3 ΔC/ΔC mouse model of ASD, and their underlying striatal alterations, at 10 weeks, 20 weeks, and 40 weeks. We highlighted that motor stereotypies worsened at 40 weeks possibly carried by earlier striatal medium spiny neurons (MSN) alterations in GABAergic transmission and morphology. Moreover, we report that 20 weeks could be a critical time-point in the striatal-related ASD physiopathology, and we suggest that MSN alterations may not be the direct consequence of developmental issues, but rather be a consequence of other impairments occurring earlier.
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.
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