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Author Notes:

Correspondence should be addressed to Katherine W. Roche, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 35, Room 2C-903, 9000 Rockville Pike, Bethesda, MD 20892-3704., rochek@ninds.nih.gov; and Stephen F. Traynelis, Department of Pharmacology and Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA 30322., strayne@emory.edu

Author contributions: H.Y., W.L., S.F.T., and K.W.R. designed research; S.L., L.Z., H.Y., M.V., and J.D.B. performed research; M.V., A.S.-C., J.D.B., W.L., S.F.T., and K.W.R. contributed unpublished reagents/analytic tools; S.L., L.Z., H.Y., M.V., A.S.-C., W.L., S.F.T., and K.W.R. analyzed data; S.L., L.Z., H.Y., M.V., A.S.-C., W.L., S.F.T., and K.W.R. wrote the paper.

We thank Jing Zhang and Phuong Le for technical assistance and the NINDS light imaging facility for their expertise.

S.F.T. is a consultant of Janssen Pharmaceuticals, Inc., Pfizer Inc, Boehringer Ingelheim Pharma GmbH & Co. KG, and co-founder of NeurOp Inc.

The other authors declare no competing financial interest.


Research Funding:

This work was supported by the National Institute of Neurological Disorders and Stroke–National Institutes of Health (NINDS Intramural Program Grant to S.L., M.V., L.Z., A.S.-C., J.D.B., W.L. and K.W.R. and Grants NS036654 and NS092989 to S.F.T.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development–NIH (Grant R01-HD082373 to H.Y.), the National Center for Advancing Translational Sciences–NIH (Grant UL1-TR000454 to H.Y.), the National Institute on Aging–NIH (Career Transition Award R00 AG041225 to A.S.-C.), and Portuguese Foundation for Science and Technology (FCT-Fundacao para a Ciencia e a Tecnologia, Grant SFRH/BI/106010/2015 to M.V.).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • dendritic morphology
  • human diseases
  • MAGUK binding
  • NMDA receptor
  • surface expression
  • synaptic function

A Rare Variant Identified Within the GluN2B C-Terminus in a Patient with Autism Affects NMDA Receptor Surface Expression and Spine Density


Journal Title:

Journal of Neuroscience Nursing


Volume 37, Number 15


, Pages 4093-4102

Type of Work:

Article | Final Publisher PDF


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.

Copyright information:

© 2017 the authors.

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