Journal article
A Rare Variant Identified Within the GluN2B C-Terminus in a Patient with Autism Affects NMDA Receptor Surface Expression and Spine Density
The Journal of neuroscience, v 37(15), pp 4093-4102
12 Apr 2017
PMID: 28283559
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 mutationmaycontribute to the phenotype in this autism patient. Morebroadly, 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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Details
- Title
- A Rare Variant Identified Within the GluN2B C-Terminus in a Patient with Autism Affects NMDA Receptor Surface Expression and Spine Density
- Creators
- Shuxi Liu - 1Receptor Biology Section andLiang Zhou - National Institute of Neurological Disorders and StrokeHongjie Yuan - Emory UniversityMarta Vieira - NINDS, Receptor Biol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USAAntonio Sanz-Clemente - Northwestern UniversityJohn D. Badger - 1Receptor Biology Section andWei Lu - National Institute of Neurological Disorders and StrokeStephen F. Traynelis - Emory UniversityKatherine W. Roche - 1Receptor Biology Section and
- Publication Details
- The Journal of neuroscience, v 37(15), pp 4093-4102
- Publisher
- Soc Neuroscience
- Number of pages
- 10
- Grant note
- SFRH/BI/106010/2015 / Portuguese Foundation for Science and Technology (FCT-Fundacao para a Ciencia e a Tecnologia); Portuguese Foundation for Science and Technology UL1-TR000454 / National Center for Advancing Translational Sciences-NIH R00AG041225 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) R01-HD082373 / Eunice Kennedy Shriver National Institute of Child Health and Human Development-NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) R01HD082373 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) R24NS092989 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) NS036654; NS092989 / National Institute of Neurological Disorders and Stroke-National Institutes of Health (NINDS Intramural Program) UL1TR000454 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) R00 AG041225 / National Institute on Aging-NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000399440400010
- Scopus ID
- 2-s2.0-85018536730
- Other Identifier
- 991020100060604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Neurosciences