NMDA Receptor Signaling Is Important for Neural Tube Formation and for Preventing Antiepileptic Drug-Induced Neural Tube Defects

Abstract

Failure of neural tube closure leads to neural tube defects (NTDs), which can have serious neurological consequences or be lethal. Use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs in offspring by unknown mechanisms. Here we show that during neural tube formation, neural plate cells exhibit spontaneous calcium dynamics that are partially mediated by glutamate signaling. We demonstrate that NMDA receptors are important for the formation of the neural tube and that the loss of their function induces an increase in neural plate cell proliferation and impairs neural cell migration, which result in NTDs. We present evidence that the AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued with varied efficacy by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. These findings may prompt mechanistic identification of AEDs that do not interfere with neural tube formation. Neural tube defects are one of the most common birth defects. Clinical investigations have determined that the use of antiepileptic drugs during pregnancy increases the incidence of these defects in the offspring by unknown mechanisms. This study discovers that glutamate signaling regulates neural plate cell proliferation and oriented migration and is necessary for neural tube formation. We demonstrate that the widely used antiepileptic drug valproic acid interferes with glutamate signaling and consequently induces neural tube defects, challenging the current hypotheses arguing that they are side effects of this antiepileptic drug that cause the increased incidence of these defects. Understanding the mechanisms of neurotransmitter signaling during neural tube formation may contribute to the identification and development of antiepileptic drugs that are safer during pregnancy.

From Neural Tube Formation Through the Differentiation of Spinal Cord Neurons: Ion Channels in Action During Neural Development

“…Expression of these diverse types of channels appears to start at even earlier stages of neural development, before the neural tube is formed. At neural plate stages, Xenopus neuroectodermal cells exhibit Ca 2+ transients (Abdul-Wajid et al, 2015;Christodoulou and Skourides, 2015;Sequerra et al, 2018) that are mediated partially by T-type Ca 2+ channels (Abdul-Wajid et al, 2015) and by NMDA receptors, as demonstrated by our recently published study (Sequerra et al, 2018).…”

“…Genetic or pharmacological inhibition of NMDA receptor activity, including antiepileptic drugs (AEDs) leads to an increase in proliferating neural plate cells, which in turn leads to neural tube defects (NTDs). Based on Sequerra et al (2018).…”

“…Transcripts and proteins for glutamate (Root et al, 2008;Session et al, 2016;Sequerra et al, 2018) and GABA (Barker et al, 1998;Root et al, 2008;Session et al, 2016) release and reception, among many other neurotransmitters (Choi et al, 1998;Messenger et al, 1999), are detected during neural plate stages. Accordingly, the role of neurotransmitter signaling and ion channels in neural tube formation demands further investigation.…”

“…This activity may not be structured under a classical chemical synapse, but it is certainly dependent on ion channels gated by diverse mechanisms. Expression of voltage-and neurotransmitter-gated ion channels as well as transient receptor potential (TRP) channels, among others, is apparent in neural stem cells as early as neural plate stages (Abdul-Wajid et al, 2015;Sequerra et al, 2018;Spencer et al, 2019). Moreover, ion channels have been shown to participate in the formation of the brain and spinal cord during one of the first developmental steps known as neural tube formation (Abdul-Wajid et al, 2015;Sequerra et al, 2018).…”

Calcium Signaling in Vertebrate Development and Its Role in Disease

“…Pharmacologically disrupting calcium transients by blocking IP3R and other membrane-localized Ca 2+ channels, using 2ABP and nifedipine, abolished both apical constriction and movements of the neural plate towards closing. Also, this disruption reduced the width of the neural gene Sox2 expression zone and ultimately resulted in neural tube closure defects; these defects included impaired forebrain, hindbrain and midbrain in Xenopus and Ciona [ 4 , 66 , 68 , 69 , 70 , 71 ]. These results suggest that dysregulation of calcium during convergent extension and neural tube closure results in severe central nervous system defects.…”