BK-type Ca-activated K channels are targeted to the active zone of glutamatergic synapses and regulate transmitter release in rat hippocampus (Hu & al, J.Neurosci.15:9585). Since this BK channel-mediated regulation was only seen under conditions of enhanced Ca influx, we proposed that this mechanism can serve as an emergency brake that may be activate by ischemia/hypoxia. To test whether the presynaptic BK channels are modulated by reduced oxygenation, we evoked synaptic field potentials (fEPSPs) by stimulating Stratum radiatum axons in CA1 of hippocampal slices, bathed in 0.1 mM 4-aminopyridine to promote BK channel activation. We found that the effect of BK channel blockade by iberitoxin (IbTX, 100 nM) was enhanced by reduced oxygenation (p<0.05). Thus, in slices exposed to a gas mixture containing only 19% O2 (which severely reduced the fEPSP amplitude), IbTX caused a 84,4% increase in the fEPSP amplitude (n=5), whereas IbTX caused only 32,7% increase under normal conditions (95% O2; n=5). Similar results were also obtained by using whole-cell current clamp recording. In 19% O2, the average increase of 1st EPSP amplitude after IbTX application was larger (244%, n=5) than in 95% O2 (174%, n=5; p<0,01). To test whether the effect of IbTX on the EPSPs is presynaptic, we blocked the BK channels in the postsynaptic cell with a Cs-based intracellular medium during whole cell recording. Again, the average EPSP amplitude was more strongly enhanced by IbTX (100 nM) in low O2 (187 % increase, n=7) than in high O2 (101 % increase; n=7; p<0.01). These results indicate that the contribution of presynaptic BK channels to regulation of glutamate release is enhanced by reducing oxygen supply. This mechanism may help limiting brain damage during ischemia. [Supported by NFR /SFF]