Browsing by Subject "AMPA"
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Item AMPA Glutamate Receptor Trafficking in Models of Disease(2013-08) Miller, EricThe signaling between neurons in the brain underlies many crucial processes - from the beating of the heart to remembering that you have a meeting at noon. Indeed, it is proposed that changes in the way neurons communicate with each other form the basis of learning and memory. In this dissertation I will explore the ways in which neurological diseases can affect these integral neuronal functions and explain the changes on a cellular and molecular level. Deficits in AMPAR signaling are found in numerous diseases. I will explore the mechanisms of these deficits using in vitro models of three diseases: opioid-related cognitive deficits and addiction, Alzheimer's disease, and Parkinson's disease-related dementia. Background information is presented in the first chapter. In the second chapter the signaling pathways underlying morphine-induced synaptic deficits are delineated. I found that calcineurin is necessary for both functional and structural deficits in AMPAR signaling, while CaMKII is necessary for only the structural deficits. The role of tau in synaptic deficits cause by soluble Abeta; oligomers, which are found at elevated levels in Alzheimer's disease patients, are probed in the third chapter. I found that treatment with soluble Abeta; oligomers leads to phosphorylation- dependent mislocalization of tau to dendritic spines. Furthermore, treatment with soluble Abeta; oligomers leads to decreases in AMPAR signaling that require calcineurin activity and GluR1 residue S845, much like the mechanisms of AMPAR internalization in neurons treated with morphine. The fourth chapter unveils a novel role of tau and GSK3 in synaptic deficits found in neurons expressing A53T alpha-synuclein. In fact, I discovered that tau is involved in AMPAR signaling deficits found in neurons expressing A53T alpha- synuclein. Furthermore, both mislocalization of tau and synaptic deficits require phosphorylation of tau by GSK3. This dissertation shows that divergent pathways mediate structural and functional plasticity found in neurons exposed to morphine. Also, I show that deficits in AMPAR signaling in both Alzheimer's disease and Parkinson's disease involve tau mislocalization. These findings shed new light on the signaling pathways involved in AMPAR signaling deficits found in neurological diseases and provide new therapeutic targets for pharmacological interventions.Item Dynamic regulation of the NMDA receptor coagonist D-serine in the mammalian retina.(2011-09) Sullivan, Steven J.The N-methyl D-aspartate (NMDA) receptor coagonist D-serine is important in a number of different processes in the central nervous system, ranging from synaptic plasticity to disease states, including schizophrenia. In the retina, light-evoked responses of retinal ganglion cells are shaped in part by NMDA receptors which require a coagonist for activation. There is debate over whether glycine or D-serine is the endogenous coagonist of retinal ganglion NMDA receptors. I used a mutant mouse lacking functional serine racemase (SRKO), the only known D-serine synthesizing enzyme in mammals, to show that retinal ganglion cells depend on D-serine for NMDAR activation (chapter 1). Most changes in NMDA receptor currents during synaptic activity have been attributed to glutamate fluctuations against a steady background of coagonist, excluding the possibility of dynamic coagonist release. The retina is a particularly useful system to determine if coagonist release occurs in the nervous system, because it can be naturally stimulated with light. By saturating the glutamate binding site of NMDA receptors, I was able to measure coagonist release during light-evoked responses. Coagonist release was detected in retinal ganglion cell light responses and depended on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic AMPA receptors. Coagonist release was significantly lower in SRKO mice (chapter 2). By directly measuring extracellular D-serine using capillary electrophoresis, I demonstrated that D-serine can be released from the intact mouse retina through an AMPA receptor dependent mechanism (chapter 3). The collective works put forth in this thesis imply that activity-dependent modulation of D-serine availability may add an extra dimension to NMDA receptor coincidence detection in the central nervous system.