Developmental upregulation of presynaptic NCKX underlies the decrease of mitochondria-dependent posttetanic potentiation at the rat calyx of Held synapse

Abstract

The sensitivity of posttetanic potentiation (PTP) to high-frequency stimulation (HFS) steeply decays during the first 2 postnatal weeks. We investigated the underlying mechanisms for the developmental change of PTP induced by HFS (100 Hz, 2 s) at postnatal days 4–6 and 9–11 at the rat calyx of Held synapse. Low-concentration tetraphenylphosphonium (2 μM), an inhibitor of mitochondrial Na+/Ca2+exchanger, suppressed the amount of posttetanic residual Ca2+and PTP to a larger extent at the immature calyx synapse, indicating a developmental reduction of mitochondrial contribution to PTP. The higher amount of mitochondrial Ca2+uptake during HFS and consequent posttetanic residual Ca2+at the immature calyx of Held was associated with higher peak of HFS-induced Ca2+transients, most likely because the mitochondrial Ca2+uptake during HFS was supralinearly dependent on the presynaptic resting Ca2+level. Probing into the contribution of Na+/Ca2+exchangers to Ca2+clearance, we found a specific upregulation of the K+-dependent Na+/Ca2+exchanger (NCKX) activity in the mature calyx of Held. We conclude that the upregulation of NCKX limits the Ca2+buildup and inhibits mitochondrial Ca2+uptake during HFS, which in turn results in the reduction of posttetanic residual Ca2+and PTP at the mature calyx of Held synapse.