Methyl‐donor deficiency in adolescence affects memory and epigenetic status in the mouse hippocampus

Abstract

DNA methylation is one of the essential factors in the control of gene expression. Alteration of the DNA methylation pattern has been linked to various neurological, behavioral and neurocognitive dysfunctions. Recent studies have pointed out the importance of epigenetics in brain development and functions including learning and memory. Nutrients related to one-carbon metabolism are known to play important roles in the maintenance of genomic DNA methylation. Previous studies have shown that the long-term administration of a diet lacking essential one-carbon nutrients such as methionine, choline and folic acid (methyl donors) caused global DNA hypermethylation in the brain. Therefore, the long-term feeding of a methyl-donor-deficient diet may cause abnormal brain development including learning and memory. To confirm this hypothesis, 3-week-old mice were maintained on a folate-, methionine-and choline-deficient (FMCD) or control (CON) diet for 3 weeks. We found that the methyl-donor deficiency impaired both novel object recognition and fear extinction after 3 weeks of treatment. The FMCD group showed spontaneous recovery of fear that differed from that in CON. In addition, we found decreased Gria1 gene expression and specific CpG hypermethylation of the Gria1 promoter region in the FMCD hippocampus. Our data suggest that a chronic dietary lack of methyl donors in the developmental period affects learning, memory and gene expressions in the hippocampus.

Chronic vitamin E deficiency impairs cognitive function in adult zebrafish via dysregulation of brain lipids and energy metabolism

“…Additionally, neuroprotective effects may be mediated through choline’s role as a methyl-donor [57]. Therefore, our findings that choline and choline-derived methyl-donor metabolites, such as betaine and SAM, are decreased in E− brains (Figure 9B) suggests disruption of methylation reactions that could subsequently affect cognition, since methyl-donor deficiency has been found to compromise learning by disturbing DNA and/or histone methylation in the brain [58]. …”

Genetic predisposition to high anxiety- and depression-like behavior coincides with diminished DNA methylation in the adult rat amygdala

“…DNMTs transfer methyl groups from S-adenosylmethionine (SAM) to cytosine [86], so diets lacking folate or other methyl donors can impede SAM synthesis, thereby leading to DNA hypomethylation [87–89]. Depleting dietary methyl donor content has been shown to decrease DNA methylation markers in the brain [89], and impair fear memory [62, 90]. On the other hand, boosting levels of methyl donors (or SAM itself) increases DNA methylation levels in brain [91], and elicits antidepressant effects in rats and mice, such as decreased immobility in the FST and improved stress-induced anhedonia [92–95].…”

“…For instance, studies in mice found that chronic dietary methyl depletion interfered with contextual fear conditioning/memory, but did not impact anxiety-like behavior [62, 90, 102]. A study in Wistar rats combined methyl diet deficiency with chronic unpredictable stress and found that methyl donor deficiency improved chronic stress-elicited anxiety-like behavior, but did not affect FST immobility [103].…”

Vitamin E deficiency during embryogenesis in zebrafish causes lasting metabolic and cognitive impairments despite refeeding adequate diets

“…Lasting effects of reduced choline availability may partially underlie compromised cognition in the E− larvae, as demonstrated in mouse models of prenatal choline deficiency [44]. These consequences possibly are mediated by methyl donor-dependent epigenetic mechanisms [45] related to DNA methylation status, established either during the embryonic and/or larval periods.…”