The GluN2A subunit of the NMDA receptor modulates the rate of functional maturation in parvalbumin-positive interneurons

Camp, C. R.; Shapiro, L.; Vlachos, A.; Perszyk, R. E.; Shariatzadeh, N.; White, J.; Sanchez, R.; Koh, S.; Escayg, A.; Yuan, H.; McBain, C. J.; Pelkey, K. A.; Traynelis, S. F.

doi:10.1101/2021.12.29.474447

bioRxiv · 10.1101/2021.12.29.474447

The GluN2A subunit of the NMDA receptor modulates the rate of functional maturation in parvalbumin-positive interneurons

Camp, C. R.·Shapiro, L.·Vlachos, A.·Perszyk, R. E.·Shariatzadeh, N.·White, J.·Sanchez, R.·Koh, S.·Escayg, A.·Yuan, H.·McBain, C. J.·Pelkey, K. A.·Traynelis, S. F.

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Abstract

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.

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Camp, C. R., Shapiro, L., Vlachos, A., Perszyk, R. E., Shariatzadeh, N., White, J., Sanchez, R., Koh, S., Escayg, A., Yuan, H., McBain, C. J., Pelkey, K. A., Traynelis, S. F.. 2021-12-29. The GluN2A subunit of the NMDA receptor modulates the rate of functional maturation in parvalbumin-positive interneurons. https://doi.org/10.1101/2021.12.29.474447

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