Emerging roles of GluN3-containing NMDA receptors in the CNS

Key Points GluN3 subunits (A and B) were the last members of the glutamate receptor subunit family to be cloned. They assemble with GluN1 and GluN2 (A–D) subunits to form tri-heteromeric NMDA receptors (NMDARs). NMDARs containing the GluN3A subunit seem to counteract some of the well-known functions of classical NMDARs (GluN1–GluN2 di-heteromers) in long-term plasticity and synapse development. GluN3A-containing NMDARs are expressed during a narrow temporal window of early postnatal development and have been proposed to play a part in controlling the timing and extent of neural circuit refinements by acting as a 'brake' to prevent the premature strengthening and stabilization of subsets of excitatory synapses. Interactions of the carboxy-terminal domain of GluN3A with a unique set of intracellular partners are required for this function. In addition, GluN3A-containing NMDARs are much less permeable to Ca 2+ ions and relatively insensitive to voltage-dependent block by Mg 2+ compared with classical NMDARs. GluN3-containing NMDARs might also influence oligodendrocyte maturation and regulate forms of plasticity that are mediated by presynaptic NMDARs. Expression of GluN3A is reactivated in a number of neurological diseases, and emerging evidence suggests a major pathophysiological role of GluN3A in some of them, including Huntington disease, addiction and white matter damage. The therapeutic potential of targeting GluN3A-containing NMDARs or intracellular regulators of their trafficking or signalling is just beginning to be explored but might provide a rational alternative to previously attempted therapies that targeted the more ubiquitous GluN1 or GluN2 subunits. GluN3 subunits can assemble with only GluN1 subunits in heterologous cells to form surface-expressed di-heteromeric receptors that do not bind glutamate and function as excitatory glycine receptors, but the physiological significance of this function is not known. NMDA receptors that contain GluN3 subunits have several non-conventional properties that set them apart from 'classical' NMDA receptors. Pérez-Otaño and colleagues describe the important roles of these receptors in CNS development and their potential involvement in CNS disease. GluN3-containing NMDA receptors (GluN3-NMDARs) are rarer than the 'classical' NMDARs, which are composed solely of GluN1 and GluN2 subunits, and have non-conventional biophysical, trafficking and signalling properties. In the CNS, they seem to have important roles i