Year of Award
Doctor of Philosophy (PhD)
Department or School/College
Department of Biomedical and Pharmaceutical Sciences
Ken Mackie, Richard Bridges, Travis Hughes, Nathan Insel
University of Montana
N-methyl D-aspartate (NMDA) receptors are calcium permeable, glutamate-gated ion channels that mediate many forms of synaptic plasticity in the central nervous system. Due to their pivotal role in regulating synaptic plasticity, a canonical correlate of the molecular and cellular basis for learning and memory, they are implicated in the pathophysiology of various neurological disorders. Recently, advances in genome sequencing has identified the NMDA receptor to be intolerant to genetic variation, as variation often leads to disease. For example, mutations in the GluN2A subunit of the NMDA receptor are implicated in the etiology of severe epilepsy-aphasia spectrum disorders. Here we selected six gain-of-function mutations identified in patients with epilepsy-aphasia spectrum disorders and characterized their sensitivity to inhibition by GluN2A-selective negative allosteric modulators. We found that GluN2A-selective negative allosteric modulators can inhibit all the GluN2A gain-of-function-containing NMDA receptors tested, despite the location of the mutation in the receptor. However, we also found no clear evidence that transfection of GluN2A gain-of-function mutations is toxic or causes overt hyperexcitability in cultured cortical neurons or CA1 pyramidal neurons of the hippocampus. These data indicate that while GluN2A-selective negative allosteric modulators can inhibit NMDA receptors harboring GluN2A gain-of-function mutations, the presence of mutated GluN2A may not directly cause cell toxicity or hyperexcitability, at least in cultured neuronal systems.
Farnsworth, Jill Christine, "NEGATIVE ALLOSTERIC MODULATION OF NMDA RECEPTORS WITH GLUN2A GAIN-OF-FUNCTION MUTATIONS" (2019). Graduate Student Theses, Dissertations, & Professional Papers. 11461.
© Copyright 2019 Jill Christine Farnsworth