Current options for clinical treatment of ischemic strokes are currently very limited and there is a great need for interventions that can be safely administered during a period of several hours following the onset of a stroke and minimize neuronal loss. It has long been known that repetitive waves of spreading depolarizations (SD) (analogous to cortical spreading depression) occur in animal stroke models, but only recently has it been convincingly shown that SDs are very prevalent following human ischemic brain injuries. SDs produce massive ionic redistributions in neurons and glia, requiring the expenditure of metabolic energy to restore homeostasis. The repetitive SDs following ischemia place a severe additional metabolic demand on brain tissue that is already compromised by reductions in local blood flow. Thus approaches to prevent the onset and progression of these post-ischemic SD events, or even to limit their deleterious consequences, are likely to have substantial positive outcomes in clinical medicine. We have discovered that Zn2+ can play an important role in initiation of SD, and that Zn2+ release from synapses is substantial following each SD event. Zn2+ has previously been demonstrated to be toxic to both neurons and glia, and our overall hypothesis is that Zn2+ increases associated with SD make a significant contribution to injury following ischemia. We propose that this is due to Zn2+ accumulation in both neurons and astrocytes, which in turn 1) lowers the threshold for initiation of SD events and 2) serves as an upstream trigger for Ca2+ excitotoxicity. Studies in Aim 1 utilize hippocampal slice preparations from mice to evaluate the mechanisms of Zn2+ release and accumulation in single neurons and populations of astrocytes.
Aim 2 examines mechanisms by which Zn2+ can facilitate the onset of SD in hippocampal slices, including inhibition of astrocyte uptake function and up-regulation of neuronal NMDA receptor function.
Aim 3 tests the hypothesis that Zn2+ is upstream of Ca2+ deregulation following SD, and tests whether interventions that disrupt the processes identified in Aims 1&2 provide significant improvements in neuronal viability in brain slice and in vivo. Slice studies of synaptic structure and function will be complemented by in vivo studies of focal ischemia in mice.
Each aim should independently provide significant new information for the field, and when taken together, these mechanistic studies should suggest novel approaches to limit the consolidation and spread of ischemic brain injury.

Public Health Relevance

This project is designed to identify new approaches to limit the deleterious consequences of a stroke. Following a stroke, aberrant waves of brain activation contribute to the spread of injury. This project is designed to identify new approaches to limit the onset, or consequences, of these spreading waves of activation and thereby improve functional recovery.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Bosetti, Francesca
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University of New Mexico Health Sciences Center
Schools of Medicine
United States
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Aiba, Isamu; Shuttleworth, C William (2014) Characterization of inhibitory GABA-A receptor activation during spreading depolarization in brain slice. PLoS One 9:e110849
Carter, Russell E; Seidel, Jessica L; Lindquist, Britta E et al. (2013) Intracellular Zn2+ accumulation enhances suppression of synaptic activity following spreading depolarization. J Neurochem 125:673-84
Aiba, Isamu; West, Adrian K; Sheline, Christian T et al. (2013) Intracellular dialysis disrupts Zn2+ dynamics and enables selective detection of Zn2+ influx in brain slice preparations. J Neurochem 125:822-31
Carlson, Andrew P; Carter, Russell E; Shuttleworth, C William (2012) Vascular, electrophysiological, and metabolic consequences of cortical spreading depression in a mouse model of simulated neurosurgical conditions. Neurol Res 34:223-31
Aiba, Isamu; Carlson, Andrew P; Sheline, Christian T et al. (2012) Synaptic release and extracellular actions of Zn2+ limit propagation of spreading depression and related events in vitro and in vivo. J Neurophysiol 107:1032-41
Durnin, Leonie; Dai, Yanping; Aiba, Isamu et al. (2012) Release, neuronal effects and removal of extracellular *-nicotinamide adenine dinucleotide (*-NADýýý) in the rat brain. Eur J Neurosci 35:423-35
Seidel, J L; Shuttleworth, C W (2011) Contribution of astrocyte glycogen stores to progression of spreading depression and related events in hippocampal slices. Neuroscience 192:295-303
Carter, Russell E; Aiba, Isamu; Dietz, Robert M et al. (2011) Spreading depression and related events are significant sources of neuronal Zn2+ release and accumulation. J Cereb Blood Flow Metab 31:1073-84
Carter, Russell E; Weiss, John H; Shuttleworth, C William (2010) Zn²+ chelation improves recovery by delaying spreading depression-like events. Neuroreport 21:1060-4
Shuttleworth, C William (2010) Use of NAD(P)H and flavoprotein autofluorescence transients to probe neuron and astrocyte responses to synaptic activation. Neurochem Int 56:379-86

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