Vesicular glutamate release is necessary for neural tube formation

The brain and spinal cord originate from a neural tube that is preceded by a flat structure known as the neural plate during early embryogenesis. In humans, failure of the neural plate to convert into a tube by the fourth week of pregnancy leads to neural tube defects (NTDs), birth defects with serious neurological consequences. The signaling mechanisms governing the process of neural tube morphogenesis are unclear. Here we show that in Xenopus laevis embryos glutamate is released during neural plate folding in a Ca 2+ and vesicular glutamate transporter-1 (VGluT1)-dependent manner. Vesicular release of glutamate elicits Ca 2+ transients in neural plate cells that correlate with activation of Erk1/2. Knocking down or out VGluT1, globally or neural tissue-specifically, leads to NTDs and increased expression of Sox2, neural stem cell transcription factor, and neural plate cell proliferation. Exposure during early pregnancy to neuroactive drugs that disrupt these signaling mechanisms might increase the risk of NTDs in offspring. Significance Statement Neural tube defects are serious and common birth defects that occur when the neural tube fails to form and close at four weeks of pregnancy. Use of antiepileptic drugs during early pregnancy increases the risk of these defects by unclear mechanisms. Here we show that vesicular release of glutamate occurs during and is necessary for neural tube formation in Xenopus laevis embryos. This study motivates discussion on the presynaptogenic signaling mechanisms in the nervous system and their role during these early developmental stages, challenging the prevailing paradigm that neurotransmission is not apparent until neurons fully differentiate and synapses are formed.