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

• Type of Material: Article
• Authors: Chad Camp, Emory University; Anna Vlachos, National Institutes of Health; Chiara Klöckner, University of Leipzig; Ilona Krey, University of Leipzig; Tue G. Banke, Emory University; Nima Shariatzadeh, Emory University; Sarah M. Ruggiero, Children's Hospital of Philadelphia; Peter Galer, Children's Hospital of Philadelphia; Kristen L. Park, University of Colorado; Adam Caccavano, National Institutes of Health; Sarah Kimmel, National Institutes of Health; Xiaoqing Yuan, National Institutes of Health; Hongjie Yuan, Emory University; Ingo Helbig, University of Pennsylvania; Tim A. Benke, University of Colorado; Johannes R. Lemke, University of Leipzig; Kenneth A. Pelkey, National Institutes of Health; Chris J. McBain, National Institutes of Health; Stephen Traynelis, Emory University
• Language: English
• Date: 2023-09-19
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1038%2Fs42003-023-05298-9
• Title of Journal or Parent Work: Communications Biology
• Volume: 6
• Start Page: 952
• Grant/Funding Information: Research reported in this publication was supported in part by an Emory University Synergy grant awarded to S.F.T., Children’s Healthcare of Atlanta, as well as by the Emory University Integrated Cellular Imaging Core and the Emory Integrated Genomics Core, which are subsidized by the Emory University School of Medicine and part of the Emory Integrated Core Facilities. This work was supported by the following grants from the National Institutes of Health: NS113530 (C.R.C.), MH127404 (H.Y.), HD082373 (H.Y.), and NS111619 (S.F.T.). T.A.B. was supported by the Ponzio Family Chair in Neurology Research from the Children’s Hospital Colorado Foundation. K.L.P., S.F.T., J.L.R., and T.A.B. were also supported by Simon’s Foundation. I.H. was supported by The Hartwell Foundation (Individual Biomedical Research Award), NINDS (K02NS112600, U24NS120854-01, U54NS108874-04), the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Children’s Hospital of Philadelphia and the University of Pennsylvania (U54HD086984), the German Research Foundation (HE5415/3-1, HE5415/5-1, HE5415/6-1, HE5415/7-1), the National Center for Advancing Translational Sciences of the NIH (UL1TR001878), the Institute for Translational Medicine and Therapeutics’ (ITMAT) at the Perelman School of Medicine of the University of Pennsylvania, and by Children’s Hospital of Philadelphia through the Epilepsy NeuroGenetics Initiative (ENGIN).
• Keywords: Epilepsy; Ion channels in the nervous system; Neuronal development
• Research Categories: Biology, Neuroscience

Abstract

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.