Roles of Na ⁺ –Ca ²⁺ exchange and of mitochondria in the regulation of presynaptic Ca ²⁺ and spontaneous glutamate release

The release of neurotransmitter from presynaptic terminals depends on an increase in the intracellular Ca 2+ concentration ([Ca 2+ ] i ). In addition to the opening of presynaptic Ca 2+ channels during excitation, other Ca 2+ transport systems may be involved in changes in [Ca 2+ ] i .We have studied the regulation of[Ca 2+ ] i in nerve terminals of hippocampal cells in culture by the Na + –Ca 2+ exchanger and by mitochondria. In addition, we have measured changes in the frequency of spontaneous excitatory postsynaptic currents (sEPSC) before and after the inhibition of the exchanger and of mitochondrial metabolism. We found rather heterogeneous [Ca 2+ ] i responses of individual presynaptic terminals after inhibition of Na + –Ca 2+ exchange. The increase in [Ca 2+ ] i became more uniform and much larger after additional treatment of the cells with mitochondrial inhibitors. Correspondingly, sEPSC frequencies changed very little when only Na + –Ca 2+ exchange was inhibited, but increased dramatically after additional inhibition of mitochondria. Our results provide evidence for prominent roles of Na + Ca 2+ exchange and mitochondria in presynaptic Ca 2+ regulation and spontaneous glutamate release.