Dietary rescue of adult behavioral deficits in the Fmr1 knockout mouse

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.

Diet in treatment of autism spectrum disorders

“…Omega-3 (Ω-3) fatty acids (FA) are essential for normal growth and maintenance of body functions; therefore, many studies have been performed to test their efficacy in mitigation of ASD traits. Ω-3 fatty acids were administered to Fmr1 KO mice and rats and rescued ultrasonic vocalizations, social discrimination, and hyperactivity ( Nolan et al, 2020 , 2022 ; Schiavi et al, 2022 ). FXS mice treated with Ω-3 FAs also showed amelioration of alterations of emotion, social interaction, and non-spatial memory and rescue of inflammatory biomarkers (i.e., increased CD11b and CD45 in hippocampal CA1 and dentate gyrus, decreased IL-1β in CA3, increased IL-1β in prefrontal cortex, and increased TNF-α in CA1) ( Pietropaolo et al, 2014 ).…”

Effects of Soy Protein Isolate on Fragile X Phenotypes in Mice

“…These findings concur with our prior research demonstrating increased weight gain in Fmr1 KO mice fed Purina 5015 compared AIN-76A and in Fmr1 KO mice fed food pellets made from powdered soy-based infant formula compared to cow milk-based infant formula [ 11 ]. There are a few studies testing specialty diets in Fmr1 model mice [ 12 , 14 , 15 , 17 , 33 , 34 , 35 , 36 , 37 ], but to our knowledge, no one else has compared the effects of standard rodent diets or protein source on Fmr1 KO phenotypes [ 11 , 25 , 48 ]. There are published data supporting our findings of increased weight gain in response to soy in WT animals.…”

“…A PubMed search of the term “fragile X” returned over 9000 entries whereas the search terms “fragile X” AND “diet” returned only 39 papers. These publications include research on development and obesity [ 8 , 9 , 10 , 11 ], fatty acids [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], carbohydrate [ 22 ], proteins [ 23 , 24 , 25 , 26 ], dehydroepiandrosterone (DHEA) [ 27 ], folate [ 28 , 29 , 30 , 31 ], ethanol [ 32 ], lithium [ 33 ], exposome factors including bisphenol A (BPA) and polychlorinated biphenyls (PCB) [ 34 , 35 , 36 , 37 , 38 ], and the gut microbiome [ 21 , 39 , 40 ].…”

Cage effects on synaptic plasticity and its modulation in a mouse model of fragile X syndrome

“…Alterations in the total expression of various NMDAR subunits have been reported to increase [38,66,67], decrease [32,50] or not change [32,68,69] in Fmr1 KO mice (table 2). Behavioural studies in Fmr1 KO mice examining long-term memory, such as through contextual fear conditioning (CFC), have also diverged, with some studies reporting impaired fear memory [39,54,[70][71][72] and others finding intact fear memory [73][74][75][76][77] (table 3).…”