Could folic acid influence growth cone motility during the development of neural connectivity?

Perinatal dietary supplementation, together with widespread fortification of grain-based foods with synthetic folic acid (FA) has resulted in rising concentrations of unmetabolized plasma FA in pregnant women. In a recently published study we reported on experiments in which we cultured dorsal root ganglia from chick embryos in a range of FA concentrations. We found that FA inhibited neurite extension, synaptogenesis, and growth cone motility. In this commentary we consider the possible mechanism further. The effect of FA is more likely to be on motility processes of growth cones with their exploratory filapodia than on neurotrophic stimulation. Receptors present in the filapodia membrane recognize and bind to environmental guidance cues. The presence of the NMDA receptor on filapodia, and the possible competition of FA with the neurotransmitter glutamate for binding to it, resulting in perturbation of growth cone guidance, are discussed. Whether excess FA exerts its inhibitory effects by such binding competition or via some other mechanism, further investigation is needed. Sufficient intake of folate from conception through the first month of human pregnancy is essential for neural tube closure. However, our results suggest that an upper limit for FA consumption after the first month should be considered.