Dietary and genetic manipulations of folate metabolism differentially affect neocortical functions in mice

Abstract

Converging evidence suggests that folate-mediated one-carbon metabolism may modulate cognitive functioning throughout the lifespan, but few studies have directly tested this hypothesis. This study examined the separate and combined effects of dietary and genetic manipulations of folate metabolism on neocortical functions in mice, modeling a common genetic variant in the MTHFD1 gene in humans. Mutant (Mthfd1gt/+) and wildtype (WT) male mice were assigned to a folate sufficient or deficient diet at weaning and continued on these diets throughout testing on a series of visual attention tasks adapted from the 5-choice serial reaction time task. WT mice on a deficient diet exhibited impulsive responding immediately following a change in task parameters that increased demands on attention and impulse control, and on trials following an error. This pattern of findings indicates a heightened affective response to stress and/or an inability to regulate negative emotions. In contrast, Mthfd1gt/+ mice (regardless of diet) exhibited attentional dysfunction and a blunted affective response to committing an error. The Mthfd1gt/+ mice also showed significantly decreased expression levels for genes encoding choline dehydrogenase and the alpha 7 nicotinic cholinergic receptor. The effects of the MTHFD1 mutation were less pronounced when combined with a deficient diet, suggesting a compensatory mechanism to the combined genetic and dietary perturbation of folate metabolism. These data demonstrate that common alterations in folate metabolism can produce functionally distinct cognitive and affective changes, and highlight the importance of considering genotype when making dietary folate recommendations.

Deletion of one allele of Mthfd1 (methylenetetrahydrofolate dehydrogenase 1) impairs learning in mice

“…We did not measure metabolites in these pathways in the brain, but in liver we observed that betaine concentrations were decreased. This is consistent with previous observation that Mthfd1 gt/+ mice have reduced expression of the choline dehydrogenase (Chdh) gene compared to WT mice [16]; CHDH converts choline to betaine [20]. Betaine is important because of its role as a methyl donor and as an osmoregulator [21].…”

“…When the genders were analyzed separately, there was no difference between female mice, but we observed a trend towards decreased response (p = 0.06) in male mice (data not shown). This trend is in concordance with previously published reports describing behavioral impairments in male Mthfd1 gt/+ mice [16]. The Mthfd1 gt/+ mice did not show other behavioral abnormalities in any of the remaining behavioral tests, summarized in Table 1.…”

“…This level of response was maintained through the cue interval, whereas the WT mice showed a decrease in response with time. These results suggest impaired learning in Mthfd1 gt/+ mice and are consistent with behavioral findings from previous studies [16]. Interestingly, no other behavioral abnormalities were observed in male and female Mthfd1 gt/+ mice, suggesting intact locomotor and anxiety-like behavior.…”

“…These pathways are important for neurodevelopment and imbalances in the pathway affect cognitive functions [15]. In one study, adult male mice heterozygotes for the Mthfd1 gene-trap mutation were reported to exhibit attentional deficits in the five choice serial task [16].…”

Nuclear Enrichment of Folate Cofactors and Methylenetetrahydrofolate Dehydrogenase 1 (MTHFD1) Protect de Novo Thymidylate Biosynthesis during Folate Deficiency

“…2B). The observation of increased folate and MTHFD1 enrichment in the nucleus during folate deficiency provides a mechanism that accounts for the lack of a neural tube defect phenotype in Mthfd1 gt/ϩ mice and why these mice are protected from uracil accumulation in DNA and exhibit marked impairments in homocysteine remethylation (15,30,31).…”