N-methyl-D-aspartate receptors (NMDAR) are pivotal for synaptic plasticity and memory formation. Conventional NMDAR consist of heterotetrameric structures composed of GluN1 and GluN2 subunits. A third subunit, GluN3, can also assemble with NMDAR subunits giving a remarkable modification of their heteromeric structure, forming a “nonconventional” NMDAR. As a consequence, the stoichiometry and kinetic properties of the receptors are dramatically changed. Among the GluN3 family, the GluN3A subunit has been the focus of a large amount of studies during recent years. These studies reveal that GluN3A is transiently expressed during development and could play a role in the fine tuning of neuronal networks as well as associated diseases. Moreover, GluN3A distribution outside the postsynaptic densities, including perisynaptic astrocytes, places it at a strategic position to play an important role in the interactions between neurons and glial cells. This review highlights GluN3A properties and addresses its role in neurophysiology and associated pathologies. 1. Introduction The glutamatergic network during postnatal development is under a tight regulation controlled by activity. This activity is mediated by postsynaptic ionotropic glutamate receptors (iGluR), NMDAR, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPAR) as well as metabotropic glutamate receptors (mGluR) [1]. Indeed, activation of NMDAR promotes the insertion of AMPAR to the synapse, inducing long-term potentiation (LTP) [2]. In contrast, a reduction in NMDAR activation promotes the removal of AMPAR, provoking long-term depression (LTD) [3]. These functional synaptic plasticity properties are tightly linked with structural modifications such as enlargements and reductions in dendritic spine size or even formation and elimination of synapses [4–6]. These mechanisms are directly influenced by postsynaptic calcium (Ca2+) [7], and Ca2+ influx is strongly controlled by NMDAR subunit composition [8, 9]. While GluN1 and GluN2 are the main subunits forming functional NMDAR [10–12], a third member of the family, GluN3, provides entirely new properties to NMDAR kinetics, especially with regard to Ca2+ permeability [13, 14]. When coassembled with GluN1 and GluN2 subunits, GluN3A exerts a dominant-negative effect on NMDAR properties [13, 15, 16]. Its presence dominates the properties of NMDAR resulting in a negative action on NMDAR, that is, insensitivity to magnesium (Mg2+) and reduced Ca2+ influx. Predominately expressed during post-natal development, GluN3A has a strong impact on
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