Abstract
Short-term folate deficiency has been linked to cognitive defects. Given folate's role in regulating nucleotide synthesis and DNA and histone methylation, these changes are often linked to altered gene expression and might be controlled by specific regulatory networks. In our study we examined the effects of folic acid (FA) deficient or replete diets in mice, containing either no source of folate or normal FA intake, beginning post-weaning and persisting through the end of adult life at 18 months. Our goal was to assess levels of cognition in these mice using the novel object test and then connect the cognitive results to genetic changes. FA deficient mice showed significant memory impairment compared to control counterparts beginning at 5 months and persisting through 17 months, as determined by the novel object test. These deficits were associated with 363 significantly downregulated and 101 significantly upregulated genes in the deficient condition compared to the control condition in microarray analysis of hippocampal tissue. Many of these gene expression changes were determined to be specific to the hippocampus. Significant ontological categories for differential genes included nucleotide regulation, ion channel activity, and MAPK signaling; while some of these categories contain genes previously mapped to cognitive decline, other genes have not previously been associated with cognition. To determine proteins possibly involved in regulation of these genes, we performed bioinformatics analysis and found enriched motifs of for MafB and Zfp410 binding sites. These genes and enriched motifs may represent targets for treatment or investigation of memory-related diseases.
Highlights
Vitamin B9 can be found in a number of forms, referred to together as folates
We demonstrated that chronic post-weaning folate deficiency in mice produced memory deficits observed in early adulthood and in old age
Since the hippocampus is largely responsible for memory consolidation, we mapped differences in hippocampal gene expression between folic acid (FA) control and FA deficient mice and found a large number of genes to be differentially expressed in the FA deficient group
Summary
Vitamin B9 can be found in a number of forms, referred to together as folates. The two most common folates are 5-methyltetrahydrofolate (5MTHF), the biologically active form found naturally in food, and folic acid (FA), the synthetic form used in supplements and food fortification [1]. Despite mandatory folate fortification in grains in many Western cultures, a variety of circumstances can lead to chronic folate deficiency including poor diet, chronic smoking, chronic alcoholism, intestinal diseases, medications, and gene polymorphisms [19,20,21,22]. Many of these habits and diseases may lead to chronic folate deficiency for the duration of adult life, little is known, regarding the effects of this deficiency throughout adulthood. It has yet to be determined to what extent adequate folate intake during early life can protect against folate deficiency later in life, despite the fact that this scenario likely affects many people
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