Date of Award

2016

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

John J. Woodward

Second Advisor

Howard Becker

Third Advisor

Joseph B. Blumer

Fourth Advisor

L. Judson Chandler

Fifth Advisor

Arthur Riegel

Abstract

Alcoholism is a debilitating and costly disease with rates of prevalence totaling nearly 6% worldwide. Treating this disease has proven expensive and in many cases ineffective due in large part to significant gaps in our knowledge of the molecular determinants that drive the pathogenesis of the disorder. Recently, the N-methyl-D-aspartate (NMDA) receptor has emerged as a candidate site for the primary inhibitory actions of ethanol on nervous system function. This receptor is an ion channel highly expressed in the nervous system that is activated by the excitatory neurotransmitter glutamate and has been implicated in the induction of a number of cellular phenomena including the molecular underpinnings of learning and memory. Understanding how ethanol affects the function of this channel both acutely and chronically is crucial to understanding the manifestation and progression of alcohol use disorders. By employing site-directed mutagenesis and patch-clamp electrophysiology with recombinant cell-expression of mutant and wild type NMDA receptor subunit cDNAs, my research has identified a number of novel interacting sites of ethanol with the NMDA receptor complex. Additionally, this work has highlighted essential differences in both ethanol sensitivity and gating mechanics of different NMDA receptor subtypes, GluN2A- and GluN2B-containing in particular. Furthermore, by exploiting the phenomenon of bioluminescence resonance energy transfer (BRET) my work has also demonstrated that GluN2A- and GluN2B-containing NMDA receptor subtypes will co-assemble into novel receptor complexes. Further teasing the differential activity of ethanol on these NMDA receptor subtypes could lead not only to the development of novel and effective therapeutics for alcohol use disorders, but as well engender a better understanding of the molecular mechanisms that underlie learning and memory.

Rights

All rights reserved. Copyright is held by the author.

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