Ca(2+) influx–independent synaptic potentiation mediated by mitochondrial Na(+)-Ca(2+) exchanger and protein kinase C

Activity-dependent modulation of synaptic transmission is an essential mechanism underlying many brain functions. Here we report an unusual form of synaptic modulation that depends on Na(+) influx and mitochondrial Na(+)-Ca(2+) exchanger, but not on Ca(2+) influx. In Ca(2+)-free medium, tetanic stimulation of Xenopus motoneurons induced a striking potentiation of transmitter release at neuromuscular synapses. Inhibition of either Na(+) influx or the rise of Ca(2+) concentrations ([Ca(2+)](i)) at nerve terminals prevented the tetanus-induced synaptic potentiation (TISP). Blockade of Ca(2+) release from mitochondrial Na(+)-Ca(2+) exchanger, but not from ER Ca(2+) stores, also inhibited TISP. Tetanic stimulation in Ca(2+)-free medium elicited an increase in [Ca(2+)](i), which was prevented by inhibition of Na(+) influx or mitochondrial Ca(2+) release. Inhibition of PKC blocked the TISP as well as mitochondrial Ca(2+) release. These results reveal a novel form of synaptic plasticity and suggest a role of PKC in mitochondrial Ca(2+) release during synaptic transmission.