title: Intracellular Zn2+ accumulation enhances suppression of synaptic activity following spreading depolarization.
abstract: Spreading depolarization (SD) is a feed-forward wave that propagates slowly throughout brain tissue and recovery from SD involves substantial metabolic demand. Presynaptic Zn(2+) release and intracellular accumulation occurs with SD, and elevated intracellular Zn(2+) ([Zn(2+) ]i ) can impair cellular metabolism through multiple pathways. We tested here whether increased [Zn(2+) ]i could exacerbate the metabolic challenge of SD, induced by KCl, and delay recovery in acute murine hippocampal slices. [Zn(2+) ]i loading prior to SD, by transient ZnCl2 application with the Zn(2+) ionophore pyrithione (Zn/Pyr), delayed recovery of field excitatory post-synaptic potentials (fEPSPs) in a concentration-dependent manner, prolonged DC shifts, and significantly increased extracellular adenosine accumulation. These effects could be due to metabolic inhibition, occurring downstream of pyruvate utilization. Prolonged [Zn(2+) ]i accumulation prior to SD was required for effects on fEPSP recovery and consistent with this, endogenous synaptic Zn(2+) release during SD propagation did not delay recovery from SD. The effects of exogenous [Zn(2+) ]i loading were also lost in slices preconditioned with repetitive SDs, implying a rapid adaptation. Together, these results suggest that [Zn(2+) ]i loading prior to SD can provide significant additional challenge to brain tissue, and could contribute to deleterious effects of [Zn(2+) ]i accumulation in a range of brain injury models.
authors.affiliation: Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Carter
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Seidel
authors.forename: Britta E
authors.initials: BE
authors.lastname: Lindquist
authors.forename: Christian T
authors.initials: CT
authors.lastname: Sheline
authors.forename: C William
authors.initials: CW
authors.lastname: Shuttleworth
mesh_terms: D000818:Animals; D002712:Chlorides / Q000378:metabolism*; D013181:Cortical Spreading Depression / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013569:Synapses / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*; D017967:Zinc Compounds / Q000378:metabolism*
chemical_list: D002712:Chlorides; D017967:Zinc Compounds; C016837:zinc chloride