Advisor(s)
Jacques Wadiche
Committee Member(s)
Linda Wadiche
Lynn Dobrunz
Scott Cruikshank
Scott Wilson
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Neurobiology
Date of Award
6-4-2025
Abstract
AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors) are essential for synaptic transmission in the CNS, serving as key drivers of synaptic depolarization. These tetrameric receptors are composed of varying combinations of GluA1-4 subunits, encoded by the GRIA1-4 genes, which determine their unique biophysical properties. The diversity in the role of AMPARs across neuron and glial cell populations is shaped by subunit composition, post-translational modifications, and interactions with auxiliary proteins. Particularly notable is the GluA2 subunit, which modulates the receptor’s Ca2+ permeability, rectification, and polyamine sensitivity, thus playing a crucial role in synaptic plasticity and function. When receptors lack GluA2, they become permeable to Ca2+, affecting intracellular signaling, and mutations in GluA2 are associated with neurological disorders. Advances in structural and electrophysiological techniques have deepened our understanding of AMPARs, especially in their contribution to synaptic function and plasticity. Single-channel recordings and structural studies show that AMPARs possess multiple conductance states, which depend on the number of agonist-bound subunits. However, the contribution of these multiple conducting states to AMPAR Ca2+ permeability, rectification, and polyamine sensitivity has not been studied, even though AMPARs in intact circuits are exposed to a wide range of glutamate levels. This goal of this this thesis is to address how the multiple conducting states of AMPARs contribute to physiologically relevant variation in glutamate concentrations. Using synapses in the cerebellum that exhibit different glutamate concentration transients, as well as AMPARs in membrane patches and expressed in heterologous expression systems, we show glutamate concentration-dependent alters rectification and Ca2+ permeability. Thus the biophysical properties of AMPARs previously ascribed to subunit composition are modulated by glutamate concentration. By modeling AMPAR responses to varying glutamate and polyamine levels, we found that a single-conducting-state model could not explain the observed glutamate-dependent effects. Rather, a multiple-conducting-state model, which adjusts polyamine binding rates based on glutamate occupancy successfully replicated experimental data. These results provide new insight into the role of glutamate concentration in regulating AMPAR biophysical properties, likely due to shifts in the occupancy of their multiple conductance states. Although focused on AMPARs in cerebellar molecular layer interneurons and GluA1 subunits, similar effects may generalize to all AMPAR subunits. These findings have important implications for understanding the contribution of AMPARs to synaptic transmission and plasticity throughout the central nervous system. Keywords: AMPARs, GluA2 subunit, synaptic transmission, Ca2+ permeability, polyamine sensitivity, glutamate concentration, synaptic plasticity, conductance states
ProQuest ID
Recommended Citation
Banumurthy, Gokulakrishna, "The Contribution Of Multiple Conducting States To Ampa Receptor Biophysical Properties" (2025). All ETDs from UAB. 7327.
https://digitalcommons.library.uab.edu/etd-collection/7327
