Functional assessment of the NMDA receptor variant GluN2A ^R586K

Background: The N-methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate receptor that has important roles in synaptogenesis, synaptic transmission, and synaptic plasticity. Recently, a large number of rare genetic variants have been found in NMDAR subunits in people with neurodevelopmental disorders, and also in healthy individuals. One such is the GluN2A^R586K variant, found in a person with intellectual disability. Identifying the functional consequences, if any, of such variants allows their potential contribution to pathogenesis to be assessed. Here, we assessed the effect of the GluN2A^R586K variant on NMDAR pore properties. Methods: We expressed recombinant NMDARs with and without the GluN2A^R586K variant in Xenopus laevis oocytes and in primary cultured mouse neurons, and made electrophysiological recordings assessing Mg²⁺ block, single-channel conductance, mean open time and current density. Results: The GluN2A^R586K variant was not found to influence any of the properties assessed. Conclusions: Our findings suggest it is unlikely that the GluN2A^R586K variant contributes to the pathogenesis of neurodevelopmental disorder.