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
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
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.
McBain Chris J.、Vlachos Anna、Kl?ckner Chiara、Banke Tue G.、Kimmel Sarah、Yuan Xiaoqing、Park Kristen L.、Caccavano Adam、Yuan Hongjie、Benke Tim A.、Traynelis Stephen F.、Camp Chad R.、Ruggiero Sarah M、Galer Peter、Helbig Ingo、Shariatzadeh Nima、Krey Ilona、Lemke Johannes R.、Pelkey Kenneth A.
Section on Cellular and Synaptic Physiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of HealthSection on Cellular and Synaptic Physiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of HealthInstitute of Human Genetics, University of Leipzig Medical CenterDepartment of Pharmacology and Chemical Biology, Emory University School of MedicineSection on Cellular and Synaptic Physiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of HealthSection on Cellular and Synaptic Physiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of HealthUniversity of Colorado School of Medicine and Children?ˉs Hospital ColoradoSection on Cellular and Synaptic Physiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of HealthDepartment of Pharmacology and Chemical Biology, Emory University School of Medicine||Center for Functional Evaluation of Rare Variants, Emory University School of MedicineUniversity of Colorado School of Medicine and Children?ˉs Hospital ColoradoDepartment of Pharmacology and Chemical Biology, Emory University School of Medicine||Center for Functional Evaluation of Rare Variants, Emory University School of MedicineDepartment of Pharmacology and Chemical Biology, Emory University School of MedicineDivision of Neurology, Children?ˉs Hospital of Philadelphia||The Epilepsy NeuroGenetics Initiative, Children?ˉs Hospital of PhiladelphiaDepartment of Biomedical and Health Informatics, Children?ˉs Hospital of PhiladelphiaDivision of Neurology, Children?ˉs Hospital of Philadelphia||The Epilepsy NeuroGenetics Initiative, Children?ˉs Hospital of Philadelphia||Department of Biomedical and Health Informatics, Children?ˉs Hospital of Philadelphia||Department of Neurology, University of Pennsylvania Perelman School of MedicineDepartment of Pharmacology and Chemical Biology, Emory University School of MedicineInstitute of Human Genetics, University of Leipzig Medical CenterInstitute of Human Genetics, University of Leipzig Medical CenterSection on Cellular and Synaptic Physiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health
基础医学神经病学、精神病学生理学
McBain Chris J.,Vlachos Anna,Kl?ckner Chiara,Banke Tue G.,Kimmel Sarah,Yuan Xiaoqing,Park Kristen L.,Caccavano Adam,Yuan Hongjie,Benke Tim A.,Traynelis Stephen F.,Camp Chad R.,Ruggiero Sarah M,Galer Peter,Helbig Ingo,Shariatzadeh Nima,Krey Ilona,Lemke Johannes R.,Pelkey Kenneth A..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[EB/OL].(2025-03-28)[2025-04-24].https://www.biorxiv.org/content/10.1101/2021.12.29.474447.点此复制
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