Abstract
The causes and contributing factors of autism spectrum disorders (ASD) are poorly understood. One gene associated with increased risk for ASD is methylenetetrahydrofolate-reductase (MTHFR), which encodes a key enzyme in one carbon (C1) metabolism. The MTHFR 677C > T polymorphism reduces the efficiency of methyl group production with possible adverse downstream effects on gene expression. In this study, the effects of prenatal and/or postnatal diets enriched in C1 nutrients on ASD-like behavior were evaluated in Mthfr-deficient mice. Differences in intermediate pathways between the mice with and without ASD-like behaviors were tested. The findings indicate that maternal and offspring Mthfr deficiency increased the risk for an ASD-like phenotype in the offspring. The risk of ASD-like behavior was reduced in Mthfr-deficient mice supplemented with C1 nutrients prenatally. Specifically, among offspring of Mthfr+/- dams, prenatal diet supplementation was protective against ASD-like symptomatic behavior compared to the control diet with an odds ratio of 0.18 (CI:0.035, 0.970). Changes in major C1 metabolites, such as the ratios between betaine/choline and SAM/SAH in the cerebral-cortex, were associated with ASD-like behavior. Symptomatic mice presenting ASD-like behavior showed decreased levels of GABA pathway proteins such as GAD65/67 and VGAT and altered ratios of the glutamate receptor subunits GluR1/GluR2 in males and NR2A/NR2B in females. The altered ratios, in turn, favor receptor subunits with higher sensitivity to neuronal activity. Our study suggests that MTHFR deficiency can increase the risk of ASD-like behavior in mice and that prenatal dietary intervention focused on MTHFR genotypes can reduce the risk of ASD-like behavior.
Highlights
The methylene-tetrahydrofolate reductase (MTHFR)-coding gene is associated with increased risk for developmental outcomes, including autism spectrum disorder (ASD) and schizophrenia (James et al, 2006; Feng et al, 2009; Goin-Kochel et al, 2009; Mohammad et al, 2009; Vares et al, 2010; Liu et al, 2011; Schmidt et al, 2011; Guo et al, 2012; Schmidt et al, 2012; Pu et al, 2013)
Detailed results for offspring and maternal genotypes, sex and diet are presented in the Supplementary Material, Behavior Tables (Tables S1–S5)
A large proportion of the heterozygote Mthfr+/− mice showed behavioral impairment characteristic of the ASDlike phenotype that was similar to other rodent models of autism (McFarlane et al, 2008; Bozdagi et al, 2010; Silverman et al, 2011)
Summary
The MTHFR-coding gene is associated with increased risk for developmental outcomes, including ASD and schizophrenia (James et al, 2006; Feng et al, 2009; Goin-Kochel et al, 2009; Mohammad et al, 2009; Vares et al, 2010; Liu et al, 2011; Schmidt et al, 2011; Guo et al, 2012; Schmidt et al, 2012; Pu et al, 2013). The activity of MTHFR strongly affects the one-carbon (C1) metabolic pathway, which is central to cellular methylation reactions. The C1 metabolic pathway includes the folate dependent and folate independent pathways, which converge to convert homocysteine to methionine. In the folate dependent pathway, MTHFR catalyzes the reduction of methylene-tetrahydrofolate to methyl-tetrahydrofolate, which reacts with homocysteine. The folate independent pathway uses choline to produce betaine, which remethylates homocysteine. Methionine produced from either pathway is converted to S-adenosylmethionine (SAM), a universal methyl donor. Investigations of C1 metabolism in humans with the homozygous recessive MTHFR677TT (vs 677CC) polymorphism, and impaired MTHFR activity, revealed increased use of the methyl donor choline (Yan et al, 2011) or its derivative betaine (Ganz et al, 2016, 2017) to preserve methyl group homeostasis. Similar findings have been reported in Mthfr-knockout mice (Schwahn et al, 2003; Chew et al, 2011)
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