Abstract
The current study aimed to further address important questions regarding the therapeutic efficacy of omega-3 fatty acids for various behavioral and neuroimmune aspects of the Fmr1 phenotype. To address these questions, our experimental design utilized two different omega-3 fatty acid administration timepoints, compared to both standard laboratory chow controls ("Standard") and a diet controlling for the increase in fat content ("Control Fat"). In the first paradigm, post-weaning supplementation (after postnatal day 21) with the omega-3 fatty acid diet ("Omega-3") reversed deficits in startle threshold, but not deficits in prepulse inhibition, and 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 compared to the Standard diet. The post-weaning Omega-3 diet reduced hippocampal expression of IL-6 and this reduction of IL-6 was significantly associated with diminished performance in the fear conditioning task. In the perinatal experimental paradigm, the Omega-3 diet attenuated hyperactivity and acquisition of a fear response. Additionally, perinatal exposure to the Control Fat diet (similar to a "Western" diet) further diminished nonsocial anxiety in the Fmr1 knockout. 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.
Highlights
Fragile X syndrome (FXS) is a neurodevelopmental disorder resulting from a trinucleotide (CGG) repeat mutation in the fragile X mental retardation (FMR1) gene, which codes for the Fragile X mental retardation protein (FMRP)
The current study aimed to address questions regarding the therapeutic efficacy of omega-3 fatty acids for key aspects of the Fmr1 phenotype, such as whether any behavioral effects might be mediated through changes in inflammatory gene expression, whether timing matters, and how previous effects compare when referenced to a standard dietary control
Given the potential impact of hyperactivity on the findings of subsequent behavioral testing and the consistent appearance in the Fmr1 KO model, we assessed the impact of high omega-3 fatty acids on activity levels in the elevated plus maze
Summary
Fragile X syndrome (FXS) is a neurodevelopmental disorder resulting from a trinucleotide (CGG) repeat mutation in the fragile X mental retardation (FMR1) gene, which codes for the Fragile X mental retardation protein (FMRP). Mutations in FMR1 are one of the most prevalent genetic contributors to inherited intellectual disability [1] and Autism spectrum disorder (ASD) [2]. Individuals with FXS display a myriad of behavioral abnormalities, including significant cognitive dysfunction, autistic behaviors, and hyperactivity [3]. These phenotypes are often mirrored in the Fmr knockout mouse, which demonstrates significant learning impairments, hyperactivity, social impairments, and increased repetitive. Dietary rescue of Fmr knockout mouse (NS088776, awarded to JL) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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