Loss of Grin2a Causes a Transient Delay in the Electrophysiological Maturation of Hippocampal Parvalbumin Interneurons: A Possible Mechanism for Transient Seizure Burden in Patients with Null GRIN2A Variants

N-methyl-D-aspartate receptors (NMDARs) comprise a family of ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits (encoded by the GRIN1 gene) and two GluN2 subunits (encoded by the GRIN2A - GRIN2D genes). 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. To explore this new clinical finding at that circuit and cellular level, we conducted studies using Grin2a+/- and Grin2a-/- mice at various stages during neurodevelopment. 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 other GRIN genes (including Grin2b ) nor can they be attributed to perturbations in the intrinsic excitability or action-potential firing properties of CA1 pyramidal cells. 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 PV interneurons. Overall, we report that Grin2a+/+ mice reach electrophysiological maturation between the neonatal and juvenile neurodevelopmental timepoints, with Grin2a+/- mice not reaching electrophysiological maturation until preadolescence, and Grin2a-/- not reaching electrophysiological maturation until adulthood. Overall, these data may represent a molecular mechanism describing the transient nature of seizure burden in disease-associated null GRIN2A patients. ### Competing Interest Statement H.Y. and S.F.T. are co-inventors of Emory-owned intellectual property. S.F.T. is a member of the SAB for Sage Therapeutics, Eumentis Therapeutics, the GRIN2B Foundation, the CureGRIN Foundation, and CombinedBrain. S.F.T. is a consultant for GRIN Therapeutics. H.Y. is the PI on a research grant from Sage Therapeutics to Emory. S.F.T. is cofounder of NeurOp, Inc. and Agrithera. T.A.B. is a member of the SAB for GRIN2B Foundation, CureGRIN Foundation and GRIN Therapeutics; all remuneration has been made to his department. T.G.B. is PI on a research grant from Neumora to Emory University.