{"doi":"10.1101/2021.12.29.474447","title":"Loss of <i>Grin2a</i> Causes a Transient Delay in the Electrophysiological Maturation of Hippocampal Parvalbumin Interneurons: A Possible Mechanism for Transient Seizure Burden in Patients with Null <i>GRIN2A</i> Variants","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":218106,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9649,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":773918,"name":"Anna Vlachos","orcid":"0000-0002-4411-9447","position":1,"is_corresponding":false},{"id":456143,"name":"Chiara Klöckner","orcid":"0000-0003-4585-8601","position":2,"is_corresponding":false},{"id":628347,"name":"Ilona Krey","orcid":"0000-0002-9168-7615","position":3,"is_corresponding":false},{"id":815524,"name":"Tue G. Banke","orcid":"0000-0001-8417-4400","position":4,"is_corresponding":false},{"id":815928,"name":"Nima Shariatzadeh","orcid":null,"position":5,"is_corresponding":false},{"id":632139,"name":"Sarah M. Ruggiero","orcid":"0000-0002-0834-0750","position":6,"is_corresponding":false},{"id":106362,"name":"Peter D. Galer","orcid":"0000-0002-6408-0906","position":7,"is_corresponding":false},{"id":564775,"name":"Kristen Park","orcid":"0000-0001-5527-3047","position":8,"is_corresponding":false},{"id":285944,"name":"Adam Caccavano","orcid":"0000-0002-6819-533X","position":9,"is_corresponding":false},{"id":815929,"name":"Sarah Kimmel","orcid":null,"position":10,"is_corresponding":false},{"id":355202,"name":"Xiaoqing Yuan","orcid":"0000-0003-1737-3295","position":11,"is_corresponding":false},{"id":295025,"name":"Hongjie Yuan","orcid":"0000-0002-8127-7145","position":12,"is_corresponding":false},{"id":44516,"name":"Ingo Helbig","orcid":"0000-0001-8486-0558","position":13,"is_corresponding":false},{"id":278324,"name":"Tim A. Benke","orcid":"0000-0002-6969-5061","position":14,"is_corresponding":false},{"id":456160,"name":"Johannes R. Lemke","orcid":"0000-0002-4435-6610","position":15,"is_corresponding":false},{"id":247135,"name":"Kenneth A. Pelkey","orcid":"0000-0002-9731-1336","position":16,"is_corresponding":false},{"id":247150,"name":"Chris J. McBain","orcid":"0000-0002-5909-0157","position":17,"is_corresponding":false},{"id":295026,"name":"Stephen F. Traynelis","orcid":"0000-0002-3750-9615","position":18,"is_corresponding":false},{"id":295016,"name":"Chad R. Camp","orcid":"0000-0002-3415-4652","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-18T23:53:24.683898Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}