Oxygen withdrawal triggers a synchronized depolarization of rat hippocampal CA1 neurons. It is accompanied by a negative shift of the extracellular DC potential, the characteristic sign of hypoxia-induced spreading depression (HSD). Yet it is still unclear how CA1 neurons sense hypoxia and what triggers their initial hypoxic responses. Is it the mitochondrial depolarization or changes in cytosolic redox state? Sulfhydryl (SH-) oxidation and H₂O₂ postponed the onset of hypoxic spreading depression, while SH-reduction or inhibition of glutathione peroxidase hastened HSD onset. Mitochondrial uncoupling or inhibition of complexes I, III and IV also hastened HSD onset. However, blocking the mitochondrial ATP synthase by oligomycin was without effect. Thus the hastening of HSD onset upon mitochondrial uncoupling and inhibition cannot be explained by accelerated ATP depletion only. The radical scavengers trolox and ascorbate or inhibition of superoxide dismutase did not affect HSD at all. Therefore, increased levels of reactive oxygen species can be excluded to facilitate HSD onset. Rather reducing conditions were found to hasten the onset of HSD, and in fact inhibition of mitochondria or glutathione peroxidase does cause such a reducing shift due to NADH, FADH₂ and GSH accumulation. So far, we obtained evidence that BK-type KCa²⁺ channels are oxidation-sensitive targets. Reduction-sensitive molecular targets still need to be identified.

Supported by: DFG (CMPB, SFB406) and Göttingen University