Ca²⁺ influx–independent synaptic potentiation mediated by mitochondrial Na⁺-Ca²⁺ 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⁺-Ca²⁺ exchanger, but not on Ca²⁺ influx. In Ca²⁺-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 Ca²⁺ concentrations ([Ca²⁺]_i) at nerve terminals prevented the tetanus-induced synaptic potentiation (TISP). Blockade of Ca²⁺ release from mitochondrial Na⁺-Ca²⁺ exchanger, but not from ER Ca²⁺ stores, also inhibited TISP. Tetanic stimulation in Ca²⁺-free medium elicited an increase in [Ca²⁺]_i, which was prevented by inhibition of Na⁺ influx or mitochondrial Ca²⁺ release. Inhibition of PKC blocked the TISP as well as mitochondrial Ca²⁺ release. These results reveal a novel form of synaptic plasticity and suggest a role of PKC in mitochondrial Ca²⁺ release during synaptic transmission.