Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits (GRIN1) and two GluN2 subunits (GRIN2A-GRIN2D). Sequencing data shows that 43% (297/679) of all currently known NMDAR disease-associated genetic variants are within the GRIN2A gene, which encodes the GluN2A subunit. Here, we show that unlike missense GRIN2A variants, individuals affected with disease-associated null GRIN2A variants demonstrate a transient period of seizure susceptibility that begins during infancy and diminishes near adolescence. We show increased circuit excitability and CA1 pyramidal cell output in juvenile mice of both Grin2a(+/-) and Grin2a(-/-) mice. These alterations in somatic spiking are not due to global upregulation of most Grin genes (including Grin2b). Deeper evaluation of the developing CA1 circuit led us to uncover age- and Grin2a gene dosing-dependent transient delays in the electrophysiological maturation programs of parvalbumin (PV) interneurons. We report that Grin2a(+/+) mice reach PV cell electrophysiological maturation between the neonatal and juvenile neurodevelopmental timepoints, with Grin2a(+/-) mice not reaching PV cell electrophysiological maturation until preadolescence, and Grin2a(-/-) mice not reaching PV cell electrophysiological maturation until adulthood. Overall, these data may represent a molecular mechanism describing the transient nature of seizure susceptibility in disease-associated null GRIN2A patients. Null GRIN2A human patients display a largely transient seizure burden that resolves with age, which may be attributable to a transient delay in the developmental maturation of parvalbumin-positive interneurons in CA1 as is observed in Grin2a(+/-) and Grin2a(-/-) mice.

Automated summary

N-methyl-D-aspartate receptors (NMDARs) are receptors that mediate calcium-permeable excitatory neurotransmission. Genetic variants in the GRIN2A gene are associated with NMDAR diseases, and individuals with null GRIN2A variants experience transient seizure susceptibility during infancy. Studies on mice show increased circuit excitability and delayed electrophysiological maturation of inhibitory interneurons in CA1 in relation to Grin2a gene dosage.