ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2017
A Rare Variant Identified Within the GluN2B C-Terminus in a Patient with Autism Affects NMDA Receptor Surface Expression and Spine Density.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed.
- Absence seizures and sleep-wake abnormalities in a rat model of GRIN2B neurodevelopmental disorder.Epilepsia · 2025Article
- Non-ionotropic signaling through the NMDA receptor GluN2B carboxy-terminal domain drives dendritic spine plasticity and reverses fragile X phenotypes.Cell reports · 2025Article
- NMDA Receptors in Neurodevelopmental Disorders: Pathophysiology and Disease Models.International journal of molecular sciences · 2024Review
- Characterization of Mice Carrying a Neurodevelopmental Disease-Associated GluN2B(L825V) Variant.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- 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
- A Frameshift Variant of GluN2A Identified in an Epilepsy Patient Results in NMDA Receptor Mistargeting.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Disease-associated nonsense and frame-shift variants resulting in the truncation of the GluN2A or GluN2B C-terminal domain decrease NMDAR surface expression and reduce potentiating effects of neurosteroids.Cellular and molecular life sciences : CMLS · 2024Article
- Classification of missense variants in the N-methyl-d-aspartate receptor GRIN gene family as gain- or loss-of-function.Human molecular genetics · 2023Article
- Hunting for Genes Underlying Emotionality in the Laboratory Rat: Maps, Tools and Traps.Current neuropharmacology · 2023Review
- GluN2B-containing NMDARs in the mammalian brain: pharmacology, physiology, and pathology.Frontiers in molecular neuroscience · 2023Review
- The Role of Zinc and NMDA Receptors in Autism Spectrum Disorders.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Different Forms of Disorder in NMDA-Sensitive Glutamate Receptor Cytoplasmic Domains Are Associated with Differences in Condensate Formation.Biomolecules · 2022Article
- NMDA Receptor C-Terminal Domain Signalling in Development, Maturity, and Disease.International journal of molecular sciences · 2022Review
- Review
- Neurodevelopmental Disorders Associated with PSD-95 and Its Interaction Partners.International journal of molecular sciences · 2022Review
- The Cerebellar Involvement in Autism Spectrum Disorders: From the Social Brain to Mouse Models.International journal of molecular sciences · 2022Review
- Progranulin improves neural development via the PI3K/Akt/GSK-3β pathway in the cerebellum of a VPA-induced rat model of ASD.Translational psychiatry · 2022Article
- Behind the scenes: Are latent memories supported by calcium independent plasticity?Hippocampus · 2022Review
- Review
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Authors and funding
9 authors.
Funding
Abstract
NMDA receptors (NMDARs) are ionotropic glutamate receptors that are crucial for neuronal development and higher cognitive processes. NMDAR dysfunction is involved in a variety of neurological and psychiatric diseases; however, the mechanistic link between the human pathology and NMDAR dysfunction is poorly understood. Rare missense variants within NMDAR subunits have been identified in numerous patients with mental or neurological disorders. We specifically focused on the GluN2B NMDAR subunit, which is highly expressed in the hippocampus and cortex throughout development. We analyzed several variants located in the GluN2B C terminus and found that three variants in patients with autism (S1415L) or schizophrenia (L1424F and S1452F) (S1413L, L1422F, and S1450F in rodents, respectively) displayed impaired binding to membrane-associated guanylate kinase (MAGUK) proteins. In addition, we observed a deficit in surface expression for GluN2B S1413L. Furthermore, there were fewer dendritic spines in GluN2B S1413L-expressing neurons. Importantly, synaptic NMDAR currents in neurons transfected with GluN2B S1413L in GluN2A/B-deficient mouse brain slices revealed only partial rescue of synaptic current amplitude. Functional properties of GluN2B S1413L in recombinant systems revealed no change in receptor properties, consistent with synaptic defects being the result of reduced trafficking and targeting of GluN2B S1413L to the synapse. Therefore, we find that GluN2B S1413L displays deficits in NMDAR trafficking, synaptic currents, and spine density, raising the possibility that this mutation may contribute to the phenotype in this autism patient. More broadly, our research demonstrates that the targeted study of certain residues in NMDARs based on rare variants identified in patients is a powerful approach to studying receptor function.
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