Mechanisms of posttetanic potentiation and its possible role in maturation of the calyx of Held synapse

Abstract

In this work, a hitherto overlooked form of short-term plasticity was identified at the calyx of Held, a glutamatergic excitatory synapse in the auditory brainstem pathway.Brief trains of high frequency stimulation (100 Hz for 1-8 s), which were applied to the afferent fibers that give rise to the calyces of Held, induced robust potentiation of excitatory postsynaptic currents (EPSCs), following the well-known depression of synaptic transmission during high frequency trains. This transient overshoot of synaptic transmission at the calyx of Held shared many properties with posttetanic potentiation (PTP) at other synapses. At the peak of PTP, synaptic strength was increased about two-fold and the decay of PTP lasted over 10s of seconds to more than 1 minute, depending on the length of the induction train. The unchanged mEPSC amplitudes during PTP and the finding that PTP was suppressed by whole-cell recording of the nerve terminal indicate its presynaptic origin. PTP was induced more easily in synapses from young rats (postnatal days, P4 - P7) as compared to an older age group (P8 - P14), suggesting that PTP is developmentally regulated, and might play a role during the formation and/or maturation of the calyx of Held.We next investigated the possible mechanisms underlying PTP. First, we found that PTP is mediated primarily via an increase in the release probability of the vesicles in the readily releasable pool (RRP), without a significant change in the size of RRP. Second, surprisingly low (~ 80 nM at the peak of PTP), but prolonged elevations of residual [Ca2+]i in the presynaptic terminal were responsible for the induction of PTP. This high efficacy of a small residual [Ca2+]i signal during PTP, and the sensitivity of PTP to presynaptic whole-cell recording, which was accompanied by accelerated residual [Ca2+]i decay, suggested that other presynaptic intracellular messengers besides Ca2+ might also be involved in PTP. Therefore, we tested the protein kinase C / Munc-13 pathway. And indeed, different pharmacological experiments identified a role of protein kinase C in the induction of PTP at the calyx of Held.Thus, the calyx of Held represents a highly plastic synapse, which displays several forms of short-term plasticity that are very similar to those observed in other synapses of the central nervous system. The accessibility of this synapse to presynaptic recordings will allow understanding the mechanisms of short-term enhancement in the near future.