Spreading depression and related events are significant sources of neuronal Zn2+ 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(2+) is also implicated in ischemic neuronal injury. Synaptic glutamate release contributes to SD propagation, and because Zn(2+) is costored with glutamate in some synaptic vesicles, we examined whether Zn(2+) is released by SD and may therefore provide a significant source of Zn(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(2+) release was detected extracellularly by a Zn(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(2+). Synaptic Zn(2+) release was also maintained with repetitive SDs generated by microinjections of KCl under normoxic conditions. Intracellular Zn(2+) accumulation in CA1 neurons, assessed using microinjection of FluoZin-3, showed significant increases following SD that was attributed to synaptic Zn(2+) release. These results suggest that Zn(2+) is released during SDs and could provide a significant source of Zn(2+) that contributes to neurodegeneration in the postischemic period.
Department of Neurosciences University of New Mexico, Albuquerque, New Mexico, USA.
Russell E
RE
Carter
Isamu
I
Aiba
Robert M
RM
Dietz
Christian T
CT
Sheline
C William
CW
Shuttleworth
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D027682:Cation Transport Proteins; D002614:Chelating Agents / Q000494:pharmacology; D013181:Cortical Spreading Depression / Q000502:physiology*; D004492:Edetic Acid / Q000494:pharmacology; D005456:Fluorescent Dyes; D005947:Glucose / Q000172:deficiency; D002534:Hypoxia, Brain / Q000473:pathology; D007202:Indicators and Reagents; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D011083:Polycyclic Compounds; D011189:Potassium Chloride / Q000494:pharmacology; D017966:Pyramidal Cells / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D002614:Chelating Agents; C451182:FluoZin-3; D005456:Fluorescent Dyes; D007202:Indicators and Reagents; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D011083:Polycyclic Compounds; C491177:Slc30a3 protein, mouse; D011189:Potassium Chloride; D004492:Edetic Acid; D005947:Glucose; D015032:Zinc