Abstract
Folate is an essential micronutrient required for both cellular proliferation through de novo nucleotide synthesis and epigenetic regulation of gene expression through methylation. This dual requirement places a particular demand on folate availability during pregnancy when both rapid cell generation and programmed differentiation of maternal, extraembryonic, and embryonic/fetal tissues are required. Accordingly, prenatal neurodevelopment is particularly susceptible to folate deficiency, which can predispose to neural tube defects, or when effective transport into the brain is impaired, cerebral folate deficiency. Consequently, adequate folate consumption, in the form of folic acid (FA) fortification and supplement use, is widely recommended and has led to a substantial increase in the amount of FA intake during pregnancy in some populations. Here, we show that either maternal folate deficiency or FA excess in mice results in disruptions in folate metabolism of the offspring, suggesting diversion of the folate cycle from methylation to DNA synthesis. Paradoxically, either intervention causes comparable neurodevelopmental changes by delaying prenatal cerebral cortical neurogenesis in favor of late-born neurons. These cytoarchitectural and biochemical alterations are accompanied by behavioral abnormalities in FA test groups compared with controls. Our findings point to overlooked potential neurodevelopmental risks associated with excessively high levels of prenatal FA intake.
Highlights
Proper organization of the cerebral cortex depends on the undisturbed birth and migration of cortical neurons during prenatal neurogenesis
While predisposing risk genes for the aforementioned disorders have been recognized over recent years, it is evident that environmental factors may exert pathological influences on neural progenitor production and cortical neurogenesis
We focused our investigation on the cerebral cortex, in humans the primary site of higher-order functions, such as cognitive and emotional processing and central to a range of psychiatric disorders, those that first appear during childhood (Krystal and State 2014)
Summary
Proper organization of the cerebral cortex depends on the undisturbed birth and migration of cortical neurons during prenatal neurogenesis. Any disturbance of this process may result in cortical malformations that can lead to a range of neurodevelopmental disorders. Neuronal migration defects may lead to intractable childhood epilepsy (Kuzniecky 1994). Changes in neural progenitor proliferation may result in microcephaly or macrocephaly, both of which have been associated with autism spectrum disorders (ASDs) (Fombonne et al 1999). The neurodevelopmental analysis of animal models with mutations in ASD risk genes, by others and ourselves, has provided strong Safe upper limits for folate have been defined (1998), no guidelines have been put in place to prevent excessive consumption from multiple sources of fortified grains, supplemented cereals, and over-the-counter dietary supplements
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