Dissertation
THE ROLE OF OXIDATIVE STRESS IN AMPA RECEPTOR TRAFFICKING FOLLOWING ISCHEMIC STROKE
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2021
DOI:
https://doi.org/10.7273/000003359
Handle:
https://hdl.handle.net/2376/123253
Abstract
Stroke is a leading cause of disability and results in 140,000 deaths in the United States each year. Ischemic stroke occurs when blood flow to brain tissue is decreased or absent due to vessel occlusion, leading to infarction. While it is necessary to reintroduce blood flow to the infarcted area, this act also results in further damage to surrounding brain tissue by inflammation and oxidative stress, leading to delayed neuronal death within vulnerable neuronal populations, including hippocampal pyramidal neurons. During ischemia, the lack of energy available disrupts ATP-dependent processes that maintain ionic gradients, which are critical to cellular survival. Disrupting the ionic balance leads to excessive release of neurotransmitters, like glutamate, which are unable to effectively cleared from the synapses. Excessive stimulation of N-methyl-D-aspartate receptors (NMDARs) by glutamate is a contributing factor to delayed neuronal death, and multiple studies report that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) also contribute to delayed neuronal death. As a result of ischemia/reperfusion, AMPARs undergo a subunit composition switch from calcium-impermeable, GluA2-containing AMPARs, to calcium-permeable, GluA2-lacking AMPARs. This allows the AMPAR to conduct calcium which, in combination with excessive NMDAR stimulation, exacerbates cell death. We determined that there is a sex difference in the trafficking of AMPARs following oxygen glucose deprivation/reperfusion (OGD/R), an in vitro model for ischemia/reperfusion. GluA2-containing AMPARs are degraded by the lysosome in a calcium-dependent manner following OGD/R in male hippocampal slices, but AMPARs are not degraded in female hippocampal slices with OGD/R. Pharmacological inhibition of NADPH oxidase 1 rescues the OGD/R-induced degradation of GluA1 and GluA2 AMPAR subunits in males. Preventing the degradation of GluA2-containing AMPARs following ischemia/reperfusion has therapeutic implications in the treatment of stroke patients, so understanding the mechanisms at play are of utmost importance. In this dissertation I will discuss how OGD/R affects AMPARs in an ex vivo aged rodent acute hippocampal slice model and the role oxidative stress plays in the trafficking of these receptors.
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Details
- Title
- THE ROLE OF OXIDATIVE STRESS IN AMPA RECEPTOR TRAFFICKING FOLLOWING ISCHEMIC STROKE
- Creators
- Lindsay Achzet
- Contributors
- Darrell A Jackson (Advisor)Salah-uddin Ahmed (Committee Member)Christopher J Davis (Committee Member)Matthew Layton (Committee Member)Zhenjia Wang (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 235
- Identifiers
- 99900652205201842
- Language
- English
- Resource Type
- Dissertation