Year of Award

2017

Document Type

Dissertation - Campus Access Only

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Neuroscience

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Kasper B. Hansen

Commitee Members

Michael P. Kavanaugh, Richard J. Bridges, Philippe Diaz, Sarah Certel

Abstract

NMDA receptors are ligand-gated ion channels with unique features that make them central to critical processes in the central nervous system. Neural circuits have a remarkable ability to modulate NMDA receptor activation to communicate vast amounts of complex information. In this work, I explore several different mechanisms for modulating NMDA receptor activation. First, I evaluated the relationship between the frequency of an input and the magnitude of enhancement in a long term potentiation paradigm. Long term potentiation is an important NMDA receptor-mediated process that involves enhancement of synaptic efficiency. I relate the frequency dependent nature of LTP to NMDA receptor frequency facilitation, focusing on the role of Mg2+ block and glutamate transporters in mediating this process. Next, I explore NMDA receptor modulation by altering activity of the NMDA receptor coagonist, D-Ser. I ascribe transport of D-Ser to a previously overlooked transporter system, the sodium-dependent neutral amino acid transporters, ASCT1 and ASCT2. I show that ASCT1 and ASCT2 can function as exchangers of neutral amino acids, and importantly, of D-Ser. Additionally, I evaluate a novel inhibitor of ASCT1 and ASCT2 that could be a useful pharmacological tool to indirectly modulate NMDA receptor activation in the CNS. Finally, I relate structural properties of NMDA receptor subunits to differences in binding preference for a series of competitive antagonists at the NMDA receptor glutamate binding site. One of these antagonists, ST3, has 15-fold preference for GluN1/2A over GluN1/2B, a binding preference greater than that of all previously identified GluN1/2A-preferring competitive antagonists. I show that binding of ST3 is mediated by the S2 region of the GluN2A ABD with four non-conserved residues being responsible for the majority of the binding preference between GluN1/2A and GluN1/2B. Overall, the coagonist site, glutamate binding site, and Mg2+ block at the NMDA receptor work in concert to mediate the flow of critical information in our brains. Together, this work expands our understanding of the factors that modulate the activation of NMDA receptors and deepens our knowledge of the role that NMDA receptors play in synaptic transmission in the CNS.

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© Copyright 2017 Genevieve Elysian Lind