Blockade of presynaptic K ATP channels reduces the zinc-mediated posttetanic depression at hippocampal mossy fiber synapses

Zinc is one of the most abundant transition metals in the brain, being present in a variety of synaptic processes. The mossy fiber terminals in area CA3 of the hippocampus contain large amounts of vesicular zinc and have an extremely high density of ATP-sensitive potassium (KATP) channels. The activation of these channels by zinc leads to rapid hyperpolarization of these presynaptic terminals and inhibition of transmitter release. It has been previously shown that intense stimulation of the synapses between mossy fibers and CA3 pyramidal cells evokes a posttetanic depression of synaptic activity, accompanied by a decrease in presynaptic calcium and vesicular zinc signals. These results suggest a neuromodulatory role for zinc at these synapses, which could be mediated by inhibition of presynaptic voltage-dependent calcium channels (VDCCs) and/or activation of presynaptic KATP channels. In order to evaluate the contribution of the second mechanism we have applied multiple tetanic stimulations in the absence and presence of the KATP channel blocker tolbutamide. Under control conditions, it was observed that the delivery of six tetani caused a posttetanic depression of synaptic activity. In the presence of tolbutamide, the depression was smaller and had a shorter time course. A similar depression was also observed in the presynaptic zinc and calcium signals. These findings are in agreement with the hypothesis that the activation of KATP channels by tetanically released zinc leads to cell hyperpolarization and subsequent reduction of presynaptic calcium entry, followed by the inhibition of both zinc and glutamate release. Thus, these results suggest that the inhibition of mossy fiber synaptic transmission by intensely released zinc is partially mediated by the activation of KATP channels.