Abstract
Folate is an important B vitamin naturally found in the human diet and plays a critical role in methylation of nucleic acids. Indeed, abnormalities in this major epigenetic mechanism play a pivotal role in the pathogenesis of cognitive deficit and intellectual disability in humans. The most common cause of cognitive dysfunction in children is Down syndrome (DS). Since folate deficiency is very common among the pediatric population, we questioned whether chronic folate deficiency (CFD) exacerbates cognitive dysfunction in a mouse model of DS. To test this, adult Ts65Dn mice and their disomic littermates were chronically fed a diet free of folic acid while preventing endogenous production of folate in the digestive tract for a period of 8 weeks. Our results show that the Ts65Dn mouse model of DS was significantly more vulnerable to CFD in terms of plasma homocysteine and N5-methyltetrahydrofolate (5-MTHF) levels. Importantly, these changes were linked to degenerative alterations in hippocampal dendritic morphology and impaired nest building behavior in Ts65Dn mice. Based on our results, a rigorous examination of folate intake and its metabolism in individuals with DS is warranted.
Highlights
Folates comprise the essential B9 vitamin that, for mammals, must be obtained from the diet
While the Trisomy DS mouse model (Ts65Dn) group had significantly lower body weight compared to 2N mice (p < 0.001), no significant decline in body weight was detected during the study (Supplementary Figure S1)
While we found no significant impairment in the nesting behavior in 2N mice (p = 0.624), chronic folate deficiency (CFD) led to a significant (∼5 fold) reduction in hippocampal-mediated nesting behavior in Ts65Dn mice (Figure 2)
Summary
Folates comprise the essential B9 vitamin that, for mammals, must be obtained from the diet. Folate Deficiency in Down Syndrome (Hamdane et al, 2016), including memory processing For these reasons, abnormalities in folate intake or its metabolism could potentially lead to learning disabilities. It has been shown that mutations in 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene in humans led to developmental delay, brain atrophy, seizures, hypotonia and dementia. All these abnormalities have been reported in people with Down syndrome (DS; Arumugam et al, 2016). Due to the essential role of folate metabolism in cognitive function and the fact that a considerable proportion of the pediatric population is exposed to suboptimal doses of folate intake, the question that was raised was whether chronic folate deficiency (CFD) could lead to exacerbation of symptoms in individuals with cognitive disability
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