Folate is required for metabolic processes and neural development. Insuring its adequate levels for pregnant women through supplementation of grain-based foods with synthetic folic acid (FA) in order to prevent neural tube defects has been an ongoing public health initiative. However, because women are advised to take multivitamins containing FA before and throughout pregnancy, the supplementation together with natural dietary folates has led to a demographic with high and rising serum levels of unmetabolized FA. This raises concerns about the detrimental effects of high serum synthetic FA, including a rise in risk for autism spectrum disorder (ASD). Some recent studies have reported a protective effect of FA fortification against ASD, but others have concluded there is an increased risk for ASD and other negative neurocognitive development outcomes. These issues are accompanied by further health questions concerning high, unmetabolized FA levels in serum. In this review, we outline the reasons excess FA supplementation is a concern and review the history and effects of supplementation. We then examine the effects of FA on neuronal development from tissue culture experiments, review recent advances in understanding of metabolic functional blocks in causing ASD and treatment for these with alternative forms such as folinic acid, and finally summarize the conflicting epidemiological findings regarding ASD. Based on the evidence evaluated, we conclude that caution regarding over supplementing is warranted.

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The vitamin folic acid (FA) is essential for DNA synthesis, repair and methylation, and for methionine synthesis. Although it is necessary for neural development, recent studies suggest a possible link between excess maternal supplemental FA intake and adverse interferences with single-carbon metabolism and neural development. Insufficient FA early in brain development can lead to failure of the neural tube closure, but the consequences of too much intake have not been fully investigated. Plasma FA concentrations can increase greatly with dietary supplementation. To model the development of neural connectivity, we cultured dorsal root ganglia (DRGs) taken from 8-day-old chick embryos in a range of pteroylmonoglutamate (PteGlu, synthetic supplemental FA) concentrations. DRGs were cultured for 36 h, fixed and immunostained to reveal the locations of neural networks with synaptic vesicles. We found a concentration-dependent relationship with significant reduction in neurite length in PteGlu concentrations from 0.25 to 20 μM. The average total of stained synaptic areas surrounding each cultured DRG was significantly reduced as well. To further characterize the effects, we carried out time-lapse imaging of growth cones at terminals of extending neurites. We found that PteGlu reduced the area-changing activity of the growth cone, hindering its exploratory capabilities, along with a tendency to inhibit overall advancement, thus altering the ability to extend and form synapses. Our results show that PteGlu at 250 nM and higher reduces neurite extension and synapse formation in a dose-dependent manner during neurogenesis, and that its effect is mediated through inhibition of growth cone motility.

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