title: Synaptic release and extracellular actions of Zn2+ limit propagation of spreading depression and related events in vitro and in vivo.
abstract: Cortical spreading depression (CSD) is a consequence of a slowly propagating wave of neuronal and glial depolarization (spreading depolarization; SD). Massive release of glutamate contributes to SD propagation, and it was recently shown that Zn(2+) is also released from synaptic vesicles during SD. The present study examined consequences of extracellular Zn(2+) accumulation on the propagation of SD. SD mechanisms were studied first in murine brain slices, using focal KCl applications as stimuli and making electrical and optical recordings in hippocampal area CA1. Elevating extracellular Zn(2+) concentrations with exogenous ZnCl(2) reduced SD propagation rates. Selective chelation of endogenous Zn(2+) (using TPEN or CaEDTA) increased SD propagation rates, and these effects appeared due to chelation of Zn(2+) derived from synaptic vesicles. Thus, in tissues where synaptic Zn(2+) release was absent [knockout (KO) of vesicular Zn(2+) transporter ZnT-3], SD propagation rates were increased, and no additional increase was observed following chelation of endogenous Zn(2+) in these tissues. The role of synaptic Zn(2+) was then examined on CSD in vivo. ZnT-3 KO animals had higher susceptibility to CSD than wild-type controls as evidenced by significantly higher propagation rates and frequencies. Studies of candidate mechanisms excluded changes in neuronal excitability, presynaptic release, and GABA receptors but left open a possible contribution of N-methyl-d-aspartate (NMDA) receptor inhibition. These results suggest the extracellular accumulation of synaptically released Zn(2+) can serve as an intrinsic inhibitor to limit SD events. The inhibitory action of extracellular Zn(2+) on SD may counteract to some extent the neurotoxic effects of intracellular Zn(2+) accumulation in acute brain injury models.
authors: Department of Neurosciences, University of New Mexico, Albuquerque, New Mexico 87131-0001, USA.
authors: Isamu
authors: I
authors: Aiba
authors: Andrew P
authors: AP
authors: Carlson
authors: Christian T
authors: CT
authors: Sheline
authors: C William
authors: CW
authors: Shuttleworth
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D027682:Cation Transport Proteins; D002614:Chelating Agents / Q000494:pharmacology; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000502:physiology*; D004492:Edetic Acid / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010296:Parietal Lobe / Q000187:drug effects / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D015032:Zinc / Q000032:analysis / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D002614:Chelating Agents; D005029:Ethylenediamines; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C491177:Slc30a3 protein, mouse; D011189:Potassium Chloride; D004492:Edetic Acid; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine