DNA methylation is one of the essential factors in the control of the gene expression, and the alteration of DNA methylation pattern in the brain has been revealed to occur along with some kind of stress. Accumulating evidence suggests the importance of epigenetics in the developing brain and its functions including learning and memory. Nutrients related to one-carbon metabolism, such as methionine, choline and folic acids, work as methyl donors for maintaining the genomic DNA methylation. Therefore, we hypothesized that the lack of these nutrients especially in the developing brain might cause significant effect on the learning and memory via rearrangement of the DNA methylation pattern.

In this study, very low methionine containing diet with lacking choline and folate (folate, methionine and choline deficient: FMCD) was prepared to examine the effect of lacking methyl donors in the developing mice brain during postnatal 3-6 weeks on cognitive behaviors. As results, we found that FMCD diet impaired novel object recognition and contextual fear extinction followed by altered spontaneous recovery of the acquired fear. In addition, in the hippocampus of FMCD group, we found that the decreased expression of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor (AMPAR)'s subunit GluR1 gene (Gria1), and hyper-methylation of the Gria1 promoter region.

Our study suggests that the long-term administration of a diet lacking methyl-donors would affect learning and memory and gene expressions in the hippocampus. Considering the critical role of GluR1 in the memory formation, long-term methyl-donor deficient in the developing brain could be a potential risk in the pathogenesis of various neurocognitive disorders.