Intracellular Zn 2+ accumulation enhances suppression of synaptic activity following spreading depolarization

• Published in: Journal of neurochemistry Vol. 125; no. 5; pp. 673 - 684
• Main Authors: Carter, Russell E., Seidel, Jessica L., Lindquist, Britta E., Sheline, Christian T., Shuttleworth, C. William
• Format: Journal Article
• Language: English
• Published: 01.06.2013
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12237

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 ZnCl 2 application with the Zn 2+ ionophore pyrithione (Zn/Pyr), delayed recovery of field excitatory post‐synaptic potentials ( fEPSP s) 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.