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Author Notes:

Dr. Hongjie Yuan, Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Rollins Research Center, 1510 Clifton Road NE, Atlanta, GA, 30322, Phone: 404-727-1375, Fax: 404-727-0365. Email: hyuan@emory.edu

S.F.T., H.Y., W.T., D.L. designed experiments and analyzed data. W.T., D.L., and H.Y. performed biological experiments. All authors discussed the results and implications. All authors wrote the manuscript.

H.Y. is PI on a research grant from Sage Therapeutics to Emory University School of Medicine. SFT is a PI on research grants from Janssen and Biogen to Emory University, is a paid consultant for Janssen, is a member of the SAB for Sage Therapeutics, is co-founder of NeurOp Inc. and AgriThera, and receives licensing fees and royalties for software. S.F.T. is co-inventor on Emory-owned Intellectual Property that includes allosteric modulators of NMDA receptor function. The other authors declare no competing financial interest. During this work, H.Y. was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development, NIH-NICHD R01HD082373 and a grant from Sage Therapeutics; S.F.T. was supported by NIH-NINDS NS065371, R35NS111619, and R24NS092989. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Subjects:

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Pharmacology & Pharmacy
  • Neurosciences & Neurology
  • Glutamate receptors
  • Channelopathy
  • Endogenous neurosteroid
  • Translational study
  • Rescue pharmacology
  • DE-NOVO MUTATIONS
  • PREGNENOLONE SULFATE
  • RARE VARIANTS
  • D-SERINE
  • EPILEPSY
  • ENCEPHALOPATHY
  • TRAFFICKING
  • PHENOTYPE
  • SPECTRUM
  • PATIENT

Positive allosteric modulators that target NMDA receptors rectify loss-of-function GRIN variants associated with neurological and neuropsychiatric disorders

Tools:

Journal Title:

NEUROPHARMACOLOGY

Volume:

Volume 177

Publisher:

, Pages 108247-108247

Type of Work:

Article | Post-print: After Peer Review

Abstract:

N-methyl-D-aspartate receptors (NMDARs) mediate a slow component of excitatory synaptic transmission that plays important roles in normal brain function and development. A large number of disease-associated variants in the GRIN gene family encoding NMDAR GluN subunits have been identified in patients with various neurological and neuropsychiatric disorders. Many of these variants reduce the function of NMDARs by a range of different mechanisms, including reduced glutamate potency, reduced glycine potency, accelerated deactivation time course, decreased surface expression, and/or reduced open probability. We have evaluated whether three positive allosteric modulators of NMDAR receptor function (24(S)-hydroxycholesterol, pregnenolone sulfate, tobramycin) and three co-agonists (D-serine, L-serine, and D-cycloserine) can mitigate the diminished function of NMDARs harboring GRIN variants. We examined the effects of these modulators on NMDARs that contained 21 different loss-of-function variants in GRIN1, GRIN2A, or GRIN2B, identified in patients with epilepsy, intellectual disability, autism, and/or movement disorders. For all variants, some aspect of the reduced function was partially restored. Moreover, some variants showed enhanced sensitivity to positive allosteric modulators compared to wild type receptors. These results raise the possibility that enhancement of NMDAR function by positive allosteric modulators may be a useful therapeutic strategy.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/rdf).
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