Depression-like Behavior, Abnormal Neuronal Maturation and DNA Hypomethylation in Low Folate Diet-Fed Mice

Folate is one of B-vitamines that can not be synthesized de novo; therefore it must be taken by diet or supplementation. Since folate serves various biosynthesis reactions such as the synthesis of S-adenosyl methionine which is a methyl donor in DNA methylation, folate is an essential nutrition in the development and maintenance of biological functions. Previous epidemiological and clinical studies have implied that folate deficiency is one of risk factors for depression, suggesting the impact of folate on the development and maintenance in psychological functions. In the present study, we investigated the effects of folate deficiency on behavioral and neurobiological aspects. Three-week-old ddY outbred mice were fed control (AIN-93G, folic acid content 2 mg/kg) or low folate diets (folic acid content 0.07 mg/kg) and analyzed at 9-week-old. The low folate diet feeding decreased remarkably the serum folate levels, but did not affect body weight. The low folate diet-fed mice showed increased immobility in the forced swim test, interpreted as a depression-like behavior. In contrast, there are no differences between the control diet-fed and low folate diet-fed mice in spontaneous locomotor activity, social behaviors, motor coordination, spatial learning or anxiety-like behavior. In the hippocampal dentate gyrus, the number of doublecortin (an immature neuron marker) immunoreactive cells was increased and the number of NeuN (a mature neuron marker) immunoreactive newborn cells was decreased in the low folate diet-fed mice, suggesting that folate dificiency inhibits neuronal maturation in the dentate gyrus. Furthermore, DNA hypomethylation was observed in the dentate gyrus, not CA1 or CA3 subregions, of the low folate diet-fed mice. The low folate diet feeding-induced depression-like behavior, abnormal neuronal maturation and DNA hypomethylation were reversed by replacement of S-adenosyl methionine. These results suggest that folate deficiency-induced DNA hypomethylation causes abnormal neuronal maturation in the dentate gyrus. The inhibition of neuronal maturation in the dentate gyrus may be one of the biological basis of folate deficiency-induced depression-like symptoms.