June 2009

Document Type


Degree Name



Oregon Health & Science University


Brain ischemia, or lack of blood flow to the brain, causes damage to neural tissue, and is a leading cause of death and disability. Brain ischemia triggers a sequence of events, which can be classified in two phases: the first is a small rise in extracellular K+ with little change in the other principal ion concentrations, the cessation of EEG activity, and an increase in the frequency of miniature excitatory post-synaptic potentials (mEPSCs). The second phase is marked by a severe disregulation of all principal ionic gradients, an associated large and sustained ischemic depolarization, and a massive increase in extracellular glutamate concentration caused by the reversal of glutamate transporters. Because of the severity of the second phase, much ischemia research has centered on elucidating its mechanisms; however, the early phase likely plays a prominent role in delayed selective neuronal death in ischemia sensitive neurons such as the CA1 pyramidal neurons and the Purkinje cells in the cerebellum. Similarly, because of its extreme sensitivity, much ischemia research has focused on the hippocampus; however the mechanisms gleaned from the hippocampus may not extrapolate to other brain regions, especially those with fundamentally different cellular and molecular make-ups like the cerebellum. The goal of this thesis is to improve our understanding of the early events of the ischemic response generally, and to increase our understanding of ischemic responses across brain regions. I found that, like CA1 neurons in the hippocampus, ischemia causes Purkinje cells to depolarize to near 0mV. However in contrast to the hippocampus, the current that drives the Purkinje cells ischemic depolarization (ID) is generated mainly by nondesensitizing AMPA receptors. This ID current is triggered by glutamate that is released by the reversal of glutamate transporters, but unlike the hippocampus, it is also largely reduced by the removal of calcium from the extracellular solution. The mechanisms underlying early responses to ischemia were also investigated. In hippocampal CA1 neurons, ischemia causes an increase in intracellular calcium concentration ([Ca2+]c) and parallel increase in mEPSC frequency prior to the severe ionic disreguation and ischemic depolarization current that characterizes the second phase of the ischemic response. Despite occurring simultaneously, the increase in [Ca2+]c and in mEPSC frequency are independent of each other. The increase in mEPSC frequency is caused by the depolymerization of actin filaments and the increase in [Ca2+]c is glutamate-independent. Like the hippocampus, the first phase of the ischemic response in the cerebellum is marked by an increase in [Ca2+]c; however there is no increase in mEPSC frequency during the first five minutes of the response in Purkinje cells. This difference in the ischemic response could be explained by intrinsic differences in the synaptic input to each of these cells. Evoked responses in CA1 neurons induced by stimulation of CA3 axons are reduced by actin filament stabilization, due to a decrease in the probability of release. In contrast, actin filament stabilization has no effect in the parallel fiber and climbing fiber input to Purkinje cells, suggesting that actin plays a limited role in synaptic activity in these terminals. Thus, the early and late ischemic responses vary in different brain regions and this thesis has covered several gaps in the existing knowledge in the ischemia field.




Neuroscience Graduate Program


School of Medicine



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