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by claude@2026-07, 2026-07-05
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The study investigated how glutamate and functional NMDA receptors (NMDARs) contribute to early neuronal development, focusing on polarity acquisition and axonal elongation in cultured neurons that spontaneously release glutamate. Using pharmacological and genetic loss- and gain-of-function approaches, the authors found that functional NMDARs localize to the axonal compartment early in development and that NMDAR activity modulates neuronal polarization and axonal elongation antagonistically, mediated by Ca2+ release from the endoplasmic reticulum, Rac1 activation, actin cytoskeleton rearrangements at the growth cone, and Rac1-dependent regulation of physiological H2O2 production through a Rac1/NADPH oxidase complex. Optogenetic Rac1 activation promoted lamellipodia formation and H2O2 production, linking these outputs to Rac1 under conditions dependent on glutamate and NMDAR activity. A key limitation is that findings are based on cultured neurons and experimental manipulations rather than in vivo models. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
NMDA Receptors (NMDARs) have essential functions in the nervous system, including neuronal maturation, neurotransmission, synaptic plasticity, learning, and memory. Following membrane depolarization and glutamate activation, NMDARs mediate Ca 2+ influx into neurons, activating Ca 2+ signaling cascades with key roles in neuronal function. However, no studies have been reported on the roles of glutamate and NMDARs during early neuronal development. Although NMDARs classically act at the postsynaptic membrane, the present results indicate that neurons express functional NMDARs during polarity acquisition and localize them in the axonal compartment early in development; at this stage, cultured neurons spontaneously release glutamate. In addition, pharmacological and genetic experiments for NMDARs loss- and gain-of-function modulated neuronal polarization and axonal elongation antagonistically. An intracellular mechanism involving Ca 2+ release from the endoplasmic reticulum, activation of the Rho GTPase Rac1, and actin cytoskeleton rearrangements at the axonal growth cone couples these morphological changes. Moreover, NMDAR activity regulates the physiological intracellular production of hydrogen peroxide (H 2 O 2 ) via a Rac1/NADPH oxidase complex to support neuronal development. Optogenetic Rac1 activation simultaneously promoted lamellipodia formation and H 2 O 2 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. Based on these findings, we suggest that early physiological and spontaneous glutamate release activates NMDARs to promote early neuronal development before synapse formation, indicating that glutamate is necessary for neurotransmission, early neuronal development, and axonal growth.
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Abstract
NMDA Receptors (NMDARs) have essential functions in the nervous system, including neuronal maturation, neurotransmission, synaptic plasticity, learning, and memory. Following membrane depolarization and glutamate activation, NMDARs mediate Ca2+ influx into neurons, activating Ca2+ signaling cascades with key roles in neuronal function. However, no studies have been reported on the roles of glutamate and NMDARs during early neuronal development. Although NMDARs classically act at the postsynaptic membrane, the present results indicate that neurons express functional NMDARs during polarity acquisition and localize them in the axonal compartment early in development; at this stage, cultured neurons spontaneously release glutamate. In addition, pharmacological and genetic experiments for NMDARs loss- and gain-of-function modulated neuronal polarization and axonal elongation antagonistically. An intracellular mechanism involving Ca2+ release from the endoplasmic reticulum, activation of the Rho GTPase Rac1, and actin cytoskeleton rearrangements at the axonal growth cone couples these morphological changes. Moreover, NMDAR activity regulates the physiological intracellular production of hydrogen peroxide (H2O2) via a Rac1/NADPH oxidase complex to support neuronal development. 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. Based on these findings, we suggest that early physiological and spontaneous glutamate release activates NMDARs to promote early neuronal development before synapse formation, indicating that glutamate is necessary for neurotransmission, early neuronal development, and axonal growth.
Competing Interest Statement
The authors have declared no competing interest.
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