Inter-spike mitochondrial Ca2+ release enhances high frequency synaptic transmission

Key points Presynaptic mitochondria not only absorb but also release Ca2+ during high frequency stimulation (HFS) when presynaptic [Ca2+] is kept low (m) by high cytosolic Ca2+ buffer or strong plasma membrane calcium clearance mechanisms under physiological external [Ca2+]. Mitochondrial Ca2+ release (MCR) does not alter the global presynaptic Ca2+ transients. MCR during HFS enhances short-term facilitation and steady state excitatory postsynaptic currents by increasing vesicular release probability. The intra-train MCR may provide residual calcium at interspike intervals, and thus support high frequency neurotransmission at central glutamatergic synapses. Emerging evidence indicates that mitochondrial Ca2+ buffering contributes to local regulation of synaptic transmission. It is unknown, however, whether mitochondrial Ca2+ release (MCR) occurs during high frequency synaptic transmission. Confirming the previous notion that 2 mu m tetraphenylphosphonium (TPP+) is a specific inhibitor of the mitochondrial Na+/Ca2+ exchanger (mNCX), we studied the role of MCR via mNCX in short-term plasticity during high frequency stimulation (HFS) at the calyx of Held synapse of the rat. TPP+ reduced short-term facilitation (STF) and steady state excitatory postsynaptic currents during HFS at mature calyx synapses under physiological extracellular [Ca2+] ([Ca2+](o) = 1.2 mm), but not at immature calyx or at 2 mm [Ca2+](o). The inhibitory effects of TPP+ were stronger at synapses with morphologically complex calyces harbouring many swellings and at 32 degrees C than at simple calyx synapses and at room temperature. These effects of TPP+ on STF were well correlated with those on the presynaptic mitochondrial [Ca2+] build-up during HFS. Mitochondrial [Ca2+] during HFS was increased by TPP+ at mature calyces under 1.2 mm [Ca2+](o), and further enhanced at 32 degrees C, but not under 2 mm [Ca2+](o) or at immature calyces. The close correlation of the effects of TPP+ on mitochondrial [Ca2+] with those on STF suggests that mNCX contributes to STF at the calyx of Held synapses. The intra-train MCR enhanced vesicular release probability without altering global presynaptic [Ca2+]. Our results suggest that MCR during HFS elevates local [Ca2+] near synaptic sites at interspike intervals to enhance STF and to support stable synaptic transmission under physiological [Ca2+](o).

Automated summary

Presynaptic mitochondria can both absorb and release Ca2+ during high frequency stimulation, enhancing short-term facilitation and steady state excitatory postsynaptic currents by increasing vesicular release probability. The role of mitochondrial Ca2+ release via mNCX in short-term plasticity during synaptic transmission is significant for maintaining stable synaptic transmission.