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

• Dietary folate and the MTHFD1 gene were altered in mice.
• The effects of altered folate metabolism on neocortical functions were studied.
• Folate deficiency produced impulsivity when tasks changed and following errors.
• Mthfd1 mutant mice exhibited attentional dysfunction and blunted reaction to errors.
• Results are crucial for informing folate recommendations based on genotype.

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.