Year of Award
2026
Document Type
Dissertation
Degree Type
Doctor of Philosophy (PhD)
Degree Name
Neuroscience
Department or School/College
Division of Biological Sciences
Committee Chair
Kasper B. Hansen
Commitee Members
Travis Hughes, Jesse Hay, Sarah Certel, Andrew Rau
Keywords
electrophysiology, encephalopathy, NMDA
Abstract
NMDA receptors are ionotropic glutamate receptors that are widely expressed in the central nervous system and are crucial for normal brain development and function. De novo missense variants in the GRIN genes which encode NMDA receptor subunits are known to contribute to the etiology of diverse childhood encephalopathies, which are often associated with significant neurological dysfunction, including epilepsy, intellectual disability, autism spectrum disorders, and developmental delay. Functional classification of patient variants can inform optimal therapeutic approaches, but this is often complex, as variants may influence multiple aspects of receptor biology, including surface expression, channel open probability, and agonist potency, among others. Such a variant, GluN1-M706V, located in the GluN1 agonist binding domain, has been identified in multiple patients presenting with severe neurological phenotypes. We aimed to characterize effects of a recurrent diseaseassociated GluN1-M706V variant, using a combined approach of electrophysiology, molecular dynamics simulations, and neuronal morphological analysis. We demonstrate that the GluN1-M706V variant affects the concentration-response relationship of glycine in a manner which depends on the GluN2 subunit composition of the receptor. In GluN1-M706V/2A, but not GluN1-M706V/2B-D, the glycine response is slow to reach equilibrium, but this phenotype is ameliorated if the receptors are pre-exposed to saturating glycine. This effect of glycine pre-treatment is not attributable to changes in channel open probability or an increase in surface expression. Current amplitudes of GluN1-M706V/2A also increased with prolonged and repeated exposures to saturating glycine or glycine-site agonists, indicating that occupancy of the glycine site may recruit GluN1-M706V/2A receptors from a non-responsive state to a conformation capable of functional responses similar to wild-type. This effect was not observed in GluN1- M706V/2B receptors, while triheteromeric GluN1-M706V/2A/2B receptors exhibited an intermediate phenotype. These findings suggest that glycine site occupancy of GluN1- M706V/2A NMDA receptors may mitigate dysfunction of the receptor through a mechanism similar to a pharmacological chaperone. This could provide insight into therapeutic strategies for patients with the GluN1-M706V variant or similar pathogenic variations.
Recommended Citation
Cornelison, Lauren Elise, "FUNCTIONAL CHARACTERIZATION OF DISEASE-ASSOCIATED GLUN1- M706V NMDA RECEPTOR VARIANT" (2026). Graduate Student Theses, Dissertations, & Professional Papers. 12697.
https://scholarworks.umt.edu/etd/12697
© Copyright 2026 Lauren Elise Cornelison