NMDAR and glutamate control axon growth by regulating Rac1-dependent actin dynamics and H₂O₂ production

NMDA Receptors (NMDARs) have essential functions in the nervous system, including neuronal maturation, neurotransmission, synaptic plasticity, learning, and memory. However, reports regarding the roles of glutamate and NMDARs during early neuronal development are not available. Here, we present results showing that glutamate release and NMDARs regulate neuronal polarity acquisition. NMDARs loss- and gain-of-function antagonistically modulated neuronal polarization and axonal elongation. An intracellular mechanism involving Ca²⁺ release from the endoplasmic reticulum, activation of the Rho GTPase Rac1, actin cytoskeleton rearrangements at the axonal growth cone, and H₂O₂ production coupled these morphological changes. Optogenetic Rac1 activation simultaneously promoted lamellipodia formation and H₂O₂ production suggesting functional coupling between these seemingly unconnected events. The mechanism presented here involves a dual function for the Rac1 protein that depends on glutamate and NMDAR activity. We propose that glutamate and NMDARs, via a complex set of signaling pathways, promote early neuronal development and axonal growth.