Spreading depolarization (SD) is a feed-forward wave that propagates slowly throughout brain tissue and recovery from SD involves substantial metabolic demand. Presynaptic Zn2+ release and intracellular accumulation occurs with SD, and elevated intracellular Zn2+ ([Zn 2+]i) can impair cellular metabolism through multiple pathways. We tested here whether increased [Zn2+]i could exacerbate the metabolic challenge of SD, induced by KCl, and delay recovery in acute murine hippocampal slices. [Zn2+]i loading prior to SD, by transient ZnCl2 application with the Zn2+ 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 [Zn2+]i accumulation prior to SD was required for effects on fEPSP recovery and consistent with this, endogenous synaptic Zn2+ release during SD propagation did not delay recovery from SD. The effects of exogenous [Zn2+]i loading were also lost in slices preconditioned with repetitive SDs, implying a rapid adaptation. Together, these results suggest that [Zn2+]i loading prior to SD can provide significant additional challenge to brain tissue, and could contribute to deleterious effects of [Zn2+] i accumulation in a range of brain injury models. Synaptic Zn 2+ release and accumulation occurs during spreading depolarization (SD). We show here that intracellular Zn2+ accumulation significantly impairs recovery from SD, as measured by suppression of field excitatory postsynaptic potentials and DC shift durations. These effects were mediated by enhanced adenosine accumulation and A1 receptor activation. The added challenge of Zn2+ release and loading during SD may contribute to deleterious effects of Zn2+ in brain injury.
- spreading depression