Oiling the brain : omega-3 fatty acid supplementation in a mouse model of autism.

Previous work has supported the role of omega-3 fatty acids in the attenuation of certain aspects of the behavioral phenotype of the male Fmr1 knockout mouse model, a mouse model of ASD. The current study aimed to address important questions regarding the therapeutic efficacy of omega-3 fatty acids for various behavioral and neuroimmunological aspects of the Fmr1 phenotype. To address these questions, our experimental design utilized two different omega-3 fatty acid administration paradigms, compared to both standard laboratory chow controls as well as a diet controlling for the increase in fat content. In the first paradigm, post-weaning supplementation (after postnatal day 21) with omega-3 fatty acid diet reversed hyperactivity and deficits in startle threshold, but not deficits in pre-pulse inhibition, though the effect on startle threshold was not specific to the omega-3 diet. However, post-weaning supplementation with both experimental diets also impaired acquisition of a fear response, recall of the fear memory and contextual fear conditioning. As hypothesized, post-weaning treatment with omega-3 fatty acids reduced hippocampal expression of IL-6 and this reduction of IL-6 was significantly associated with diminished performance in the fear conditioning task, specifically implicating this signaling molecule in these behavioral deficits. In the second experimental paradigm, prenatal supplementation with omega-3’s attenuated hyperactivity, pre-pulse inhibition, and acquisition of a fear response. While prenatal omega-3 treatment had a positive impact on behavior, prenatal exposure to the control fat diet (i.e. “Western” diet) exacerbated diminished nonsocial anxiety in the Fmr1 knockout. The improvements in acquisition of a fear response seen in this paradigm were significantly associated with diminished hippocampal expression of BDNF and IL-1β. Finally, as preliminary evidence of the potential sex-specificity of this manipulation, prenatal treatment with both dietary manipulations improved diminished spectral purity of ultrasonic vocalizations in female homozygous Fmr1 knockouts, but not male knockouts, on PD9. Taken together, this study provides significant evidence that dietary fatty acids throughout the lifespan can significantly impact the behavioral and neuroimmune phenotype of the Fmr1 knockout model and supports the further development of this novel pharmaceutical alternative.