Spreading depression and related events are significant sources of neuronal Zn super(2+) release and accumulation

Spreading depression (SD) involves coordinated depolarizations of neurons and glia that propagate through the brain tissue. Repetitive SD-like events are common following human ischemic strokes, and are believed to contribute to the enlargement of infarct volume. Accumulation of Zn super(2+) is also implicated in ischemic neuronal injury. Synaptic glutamate release contributes to SD propagation, and because Zn super(2+) is costored with glutamate in some synaptic vesicles, we examined whether Zn super(2+) is released by SD and may therefore provide a significant source of Zn super(2+) in the postischemic period. Spreading depression-like events were generated in acutely prepared murine hippocampal slices by deprivation of oxygen and glucose (OGD), and Zn super(2+) release was detected extracellularly by a Zn super(2+)-selective indicator FluoZin-3. Deprivation of oxygen and glucose-SD produced large FluoZin-3 increases that propagated with the event, and signals were abolished in tissues from ZnT3 knockout animals lacking synaptic Zn super(2+). Synaptic Zn super(2+) release was also maintained with repetitive SDs generated by microinjections of KCl under normoxic conditions. Intracellular Zn super(2+) accumulation in CA1 neurons, assessed using microinjection of FluoZin-3, showed significant increases following SD that was attributed to synaptic Zn super(2+) release. These results suggest that Zn super(2+) is released during SDs and could provide a significant source of Zn super(2+) that contributes to neurodegeneration in the postischemic period.