The GluN2A Subunit of the NMDA Receptor Modulates the Rate of Functional Maturation in Parvalbumin-positive Interneurons

N-methyl-D-aspartate receptors are glutamate-gated, calcium-permeable ion channels involved in a host of normal brain functions, including neuronal development. Traditionally, the GluN2A subunit, encoded by the GRIN2A gene, is thought to signal brain and circuit maturation, given its unique expression pattern where transcripts are low embryonically and then significantly increase during preadolescence in mice. Advances in whole exome sequencing have identified mutations in the GRIN2A gene to be causal to several neuropathological diseases, including epilepsy and intellectual delay. More specifically, 56% of GRIN2A mutations are loss-of-function, displaying diminished receptor function and/or surface expression, with Grin2a--/- mice have been reported as having signatures of epileptiform activity. However, little is understood regarding GluN2A's impact on neurodevelopmental and how its absence may the GABAergic interneuron network. Our data show that Grin2a -/- mice contain 33% more parvalbumin+ interneurons in the CA1 region of the hippocampus during preadolescence and adulthood. This increase in GABAergic interneuron cell density appears to be unique to parvalbumin+ cells, as cholecystokinin+ and somatostatin+ interneurons are unchanged across Grin2a-/- and wildtype mice. Despite an increased cell count, colocalization staining for parvalbumin+ synaptic densities and measures of parvalbumin cell-specific tonic inhibition remains unchanged in preadolescence and increases as the animal ages, suggesting delayed maturation. In addition, parvalbumin+ cells from preadolescent Grin2a-/- mice exhibit immature intrinsic and firing properties, such as an increased membrane time constant and input resistance, lower threshold for depolarization-induced block, and longer action potential half-widths than age-matched WT controls, all of which become corrected in adulthood. The sum of these data suggest that the GluN2A subunit is involved in promoting cues for interneuron apoptosis during development, as well as influencing the rate of parvalbumin+ cell functional maturation. The ramifications of these abnormalities are still underexplored, but likely generate a vulnerability time window during preadolescence in which an epileptiform network can manifest. Viral strategies aimed at reintroduction of the GRIN2A gene during this critical time window could represent a viable gene therapy option for loss-of-function GRIN2A EE patients. © FASEB.