ArticleBrain : a journal of neurology2025
Synaptic dysregulation in a mouse model of GRIN2D developmental and epileptic encephalopathy.
Article in Brain : a journal of neurology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- GluN2D NMDA Receptors: Bridging Physiology and Pathology.Biological psychiatry · 2026Review
- Development ofMolecular therapy. Advances · 2026Article
- A mouse model of GRIN2D developmental and epileptic encephalopathy recapitulates the human disease.Brain : a journal of neurology · 2026Article
- Time-resolved phenotyping of seizure evolution in developmental and epileptic encephalopathy: insights and gaps from the CYFIP2 Arg87Cys mouse model.Frontiers in synaptic neuroscience · 2026Review
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28 authors.
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Abstract
Gain-of-function (GoF) variants in the GRIN2D gene, encoding the GluN2D subunit of the N-methyl-D-aspartate receptor (NMDAR), cause a severe developmental and epileptic encephalopathy (DEE) characterized by intractable seizures, hypotonia and neurodevelopmental delay. We generated mice carrying the GoF V664I variant, orthologous to V667I, which is present in ∼25% of GRIN2D-DEE patients. Heterozygous mutant mice demonstrate behavioural, neuroanatomical and electrophysiological abnormalities. Lethal convulsive seizures are observed beginning at postnatal Day 17. As adults, heterozygotes display abundant and prolonged runs of spike-wave discharges (SWD) that often persist for minutes. The SWD epochs consist of different populations, differentiated by frequency and association with time-locked behavioural arrest. V664I mutant neurons have enlarged presynaptic terminals and increased synaptic distance. Functional analysis reveals increased inhibitory synaptic activity without changes in NMDAR decay kinetics or presynaptic plasticity in CA1 neurons, and analysis of hippocampal local field potentials shows a 1.5-fold increase in evoked responses and a 1.7-fold increase in action potential generation. Notably, expression of V664I in GABAergic interneurons, but not excitatory forebrain neurons, is sufficient to recapitulate the severe electroclinical phenotype. Altogether, our studies show that altered NMDAR function in inhibitory neurons plays a prominent role in DEE associated with GRIN2D GoF variants, suggesting that targeted genetic treatment may represent a path forward to successful therapeutic intervention.
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