Mitochondrial Ca2+ buffering regulates synaptic transmission between retinal amacrine cells

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The diverse functions of retinal amacrine cells are reliant on the physiological properties of their synapses. Here we examine the role of mitochondria as Ca2+ buffering organelles in synaptic transmission between GABAergic amacrine cells. We used the protonophore p-trifluoromethoxy-phenylhydrazone (FCCP) to dissipate the membrane potential across the inner mitochondrial membrane that normally sustains the activity of the mitochondrial Ca2+ uniporter. Measurements of cytosolic Ca2+ levels reveal that prolonged depolarization-induced Ca2+ elevations measured at the cell body are altered by inhibition of mitochondrial Ca2+ uptake. Furthermore, an analysis of the ratio of Ca2+ efflux on the plasma membrane Na-Ca exchanger to influx through Ca2+ channels during voltage steps indicates that mitochondria can also buffer Ca2+ loads induced by relatively brief stimuli. Importantly, we also demonstrate that mitochondrial Ca2+ uptake operates at rest to help maintain low cytosolic Ca2+ levels. This aspect of mitochondrial Ca2+ buffering suggests that in amacrine cells, the normal function of Ca2+-dependent mechanisms would be contingent upon ongoing mitochondrial Ca2+ uptake. To test the role of mitochondrial Ca2+ buffering at amacrine cell synapses, we record from amacrine cells receiving GABAergic synaptic input. The Ca2+ elevations produced by inhibition of mitochondrial Ca2+ uptake are localized and sufficient in magnitude to stimulate exocytosis, indicating that mitochondria help to maintain low levels of exocytosis at rest. However, we found that inhibition of mitochondrial Ca2+ uptake during evoked synaptic transmission results in a reduction in the charge transferred at the synapse. Recordings from isolated amacrine cells reveal that this is most likely due to the increase in the inactivation of presynaptic Ca2+ channels observed in the absence of mitochondrial Ca2+ buffering. These results demonstrate that mitochondrial Ca2+ buffering plays a critical role in the function of amacrine cell synapses.

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Journal of Neurophysiology

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