The effect of dietary folate deficiency and age on methylation metabolites, neurotransmitters, and behavior in mice.

Abstract

Severe folate deficiency caused by inborn errors of metabolism has profound deleterious effects in the CNS such as mental retardation, psychiatric disorders, seizures and myelopathy. Mild folate deficiency, due to dietary insufficiency, drugs, or a common mutation in the gene encoding methylenetetrahydrofolate reductase (MTHFR C677T), are associated with an increased risk for depression and dementia, especially in the aging population. The metabolism of folate is intimately linked with the synthesis of S-adenosylmethionine (SAM), the sole source of methyl groups required in methyltransferase reactions. S-adenosylhomocysteine (SAH), a product of methylation reactions, accumulates in folate deficiency due to increased conversion from homocysteine. Recent studies have linked hyperhomocysteinemia and hypomethylation to gene activity, as well as methylation dependent post-translational modification of proteins and neurotransmitter metabolism in depression and dementia. To better define the role of folate deficiency in CNS function, we fed young and old C57BL/6J mice folate deficient diets for 3 months and old heterozygous tg-MTHFR mice a low folate diet for 6 months. Mice were tested for grip strength, coordination, open field activity, and spatial memory. After treatment mice were sacrificed by CO2 asphyxiation or microwave radiation. Blood, peripheral and regional brain tissues were processed for the analysis of methylation and neurotransmitter metabolites. Age did not influence brain methylation metabolites in C57BL/6J mice. Low folate and folate deficient diets decreased the SAM/SAH ratio, an indicator of methylation status in most brain regions from C57BL/6J and heterozygous tg-MTHFR mice. Overall, the effects of folate deficiency were not exacerbated by age in C57BL/6J mice. Brain methylation metabolites differed significantly depending on the method of sacrifice. Specifically, folate deficiency decreased SAM in mice sacrificed by microwave radiation and increased SAH in mice sacrificed by asphyxiation. Folate deficiency reduced dopamine and serotonin turnover in several brain regions although the levels of the parent neurotransmitters were unaffected. Choline and acetylcholine levels were reduced by folate deficiency in the mid-brain. Folate deficiency impaired open field behavior, but did not have any significant effect on spatial memory. These studies help to further our understanding of the mechanisms involved in folate deficiency on CNS function in the aging brain.