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 (<500 nm) 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 μm 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°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°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. Key points: Presynaptic mitochondria not only absorb but also release Ca2+ during high frequency stimulation (HFS) when presynaptic [Ca2+] is kept low (<500 nm) 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. [ABSTRACT FROM AUTHOR]