ArticleBrain : a journal of neurology2020
Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice.
Article in Brain : a journal of neurology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 80 citations in OpenAlex.
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- Context-dependent NMDA receptor dysfunction predicts seizure treatment in mice with human GluN1 variant.iScience · 2026Article
- A mouse model of GRIN2D developmental and epileptic encephalopathy recapitulates the human disease.Brain : a journal of neurology · 2026Article
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- Deciphering the role of CAPZA2 in neurodevelopmental disorders: insights from mouse models.Communications biology · 2025Article
- Ligand distances as key predictors of pathogenicity and function in NMDA receptors.Human molecular genetics · 2025Article
- Tonic-clonic seizures induce hypersomnia and suppress rapid eye movement sleep in mouse models of epilepsy.Sleep advances : a journal of the Sleep Research Society · 2025Article
- Molecular Insights of Drug Resistance in Epilepsy: Multi-omics Unveil.Molecular neurobiology · 2025Review
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- GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics.Molecular diversity · 2024Review
- Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights.Journal of neurology · 2024Review
- Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology.Physiological research · 2024Review
- Rescuing tri-heteromeric NMDA receptor function: the potential of pregnenolone-sulfate in loss-of-function GRIN2B variants.Cellular and molecular life sciences : CMLS · 2024Article
- Perisylvian and Hippocampal Anomalies in Individuals With PathogenicNeurology. Genetics · 2024Article
- De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor.Cellular and molecular life sciences : CMLS · 2024Article
- Selective Cell-Surface Expression of Triheteromeric NMDA Receptors.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Rare genetic brain disorders with overlapping neurological and psychiatric phenotypes.Nature reviews. Neurology · 2024Review
- Identification of early Alzheimer's disease subclass and signature genes based on PANoptosis genes.Frontiers in immunology · 2024Article
Corrections and comments
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Authors and funding
26 authors at 4 institutions in 2 countries.
Funding
Abstract
NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in GRIN2A encoding the GluN2A subunit are associated with a spectrum of disorders, ranging from mild speech and language delay to intractable neurodevelopmental disorders, including but not limited to developmental and epileptic encephalopathy. A de novo missense variant, p.Ser644Gly, was identified in a child with this disorder, and Grin2a knock-in mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibited altered hippocampal morphology at 2 weeks of age, and all homozygotes exhibited lethal tonic-clonic seizures by mid-third week. Heterozygous adults displayed susceptibility to induced generalized seizures, hyperactivity, repetitive and reduced anxiety behaviours, plus several unexpected features, including significant resistance to electrically-induced limbic seizures and to pentylenetetrazole induced tonic-clonic seizures. Multielectrode recordings of neuronal networks revealed hyperexcitability and altered bursting and synchronicity. In heterologous cells, mutant receptors had enhanced NMDA receptor agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. NMDA receptor-mediated synaptic currents in heterozygous hippocampal slices also showed a prolonged deactivation time course. Standard anti-epileptic drug monotherapy was ineffective in the patient. Introduction of NMDA receptor antagonists was correlated with a decrease in seizure burden. Chronic treatment of homozygous mouse pups with NMDA receptor antagonists significantly delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of using multiple experimental modalities to model and test therapies for severe neurodevelopmental disorders, while revealing significant biological complexities associated with GRIN2A developmental and epileptic encephalopathy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.