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EDITORIAL FOCUS
PTP of synaptic inputs is a long studied form of synaptic plasticity, entailing an increase of synaptic strength for up to several minutes after prolonged tetanic stimulation. PTP was first reported in 1941 by Feng in a series of pioneering experiments on the frog neuromuscular junction (NMJ) (Feng 1941
). Remarkably, this solitary scientist carried out this work in his Peking lab while war raged at his doorstep. Subsequent studies of the NMJ revealed that the magnitude of PTP was dependent on the number of stimuli in the tetanus, that PTP could be induced independently of Na+ influx, that the time course of PTP decay was accelerated at higher temperatures, and that PTP was associated with an intra-terminal accumulation of Ca2+ during the tetanus (Rosenthal 1969; Weinreich 1971). It was concluded that PTP could be quantitatively accounted for by an increase in release probability rather then an increase in the readily releasable pool of quanta.
Later studies used the crayfish NMJ where a large nerve terminal allows paired recordings of the presynaptic terminal and postsynaptic muscle (Wojtowicz and Atwood 1985) and imaging of ionic changes in the presynaptic terminal (Delaney and Tank 1994; Zhong et al., 2001). These studies revealed that PTP involves a prolonged rise in Na+ and Ca2+ within the terminal, without significant changes in the presynaptic action potential waveform after the tetanus. However, little is known about the underlying cellular mechanisms that trigger PTP besides the notion that presynaptic Ca2+ signaling and possibly phosphorylations are involved (Brager et al. 2003). Three recent publications have begun to tackle this issue anew using the calyx of Held synapse (Habets and Borst 2005, 2006; Korogod et al. 2005) in the mammalian brain stem where paired recordings are also feasible.
PTP exhibits an apparent Ca2+ sensitivity in the nano- to low micromole range during its decay, which coincides with an increase in mini-excitatory postsynaptic current (EPSC) frequency. In addition, the ease of induction of PTP varies during development, with increasingly more prolonged stimulation needed for more mature synapses (Korogod et al. 2005) maybe due to the increased expression of Ca2+-binding proteins (Felmy and Schneggenburger 2004). Interestingly, PTP could not be induced during whole cell patch clamp of the presynaptic terminal but could again be induced after withdrawal of the patch pipette (Korogod et al. 2005). This remarkable resurrection of PTP, after a few minutes of resting the intact calyx, argues for the necessity of a small regenerative soluble messenger to induce or maintain PTP. In fact, during paired whole cell recordings at this synapse, one observes only posttetanic depression after a tetanus (Forsythe et al. 1998). An apparent discrepancy between recent studies concerns the time course of PTP with Habets and Borst (2005) finding that PTP decays in the range of 
10 min, whereas Korogod et al. (2005) reported a decay time course of maximally 1 min. This may be due to the different induction protocols: 20 Hz for 5 min (Habets and Borst 2005) and 100 Hz for 2–10 s for Korogod et al. (2005). Another disagreement was the change in vesicle pool size after PTP. Habets and Borst (2005) found a 30% increase, whereas Korogod et al. (2005) find no significant change. Again, this may be due to the different induction protocols. Nevertheless, both groups agree that PTP is mostly due to an increased release probability.
The new work of Habets and Borst (2006) adds an important piece to the puzzle of PTP. However, several key questions remain unresolved. At other synapses, AP-broadening is a powerful mechanism for increasing transmitter release (Geiger and Jonas 2000). Habets and Borst (2006) suggest that AP-broadening may play a role in PTP. However, substantial AP broadening was not observed before at the calyx, at least for short stimulus trains (Korogod et al. 2005). In this respect, it would be of interest to know how much AP-broadening is necessary to increase the Ca2+ influx by 15% and if such AP-broadening would be detectable. Alternatively, Ca2+ currents could be increased by a Ca2+-dependent facilitation without substantially altering the AP-half-width. Other unexplained observations are the increases in two distinct transmission delays. The time between stimulation and arrival of the AP is apparently prolonged due to a change in membrane excitability. In addition, the synaptic delay itself is increased. The authors speculate that AP broadening could lead to longer synaptic delays by altering the kinetics of Ca2+ influx. However, it remains possible that the increase in delay is independent of AP broadening. Clearly, more studies are needed to elucidate these results, especially because PTP at the avian ciliary ganglion calyx synapse does not involve presynaptic AP broadening (Martin and Pilar 1964).
Habets and Borst (2006) also found that Ca2+ buffering affects the strength of PTP because PTP was nearly an order of magnitude weaker when Oregon Green bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (OGB) was used than when the lower affinity buffer Fluo-4 was employed. The affinity of the buffer will also affect the Ca2+ signal during the tetanic induction period of PTP. So it may be important to separate the effects of the Ca2+ signals during tetanic induction leading to PTP from the elevated basal Ca2+ signal that remains during the PTP itself. Fluo-4, a fast buffer, is supposed to extend the time course of PTP, so it might become saturated during the induction period leading to an overshoot of the Ca2+ concentration, whereas OGB might be more effective in buffering the Ca2+ signal during tetanic stimulation. This putative overshoot of Ca2+ during tetanic induction might trigger intracellular signaling cascades leading to PTP. If so, OGB or EGTA-like buffers might reduce PTP via a more efficient buffering during the tetanus. This might indicate that the Ca2+ signal during tetanic stimulation is probably more relevant than has been recognized so far and the slow decay of elevated Ca2+ may only be necessary for PTP's maintenance. Nevertheless, in spite of all these caveats, the work by Habets and Borst (2006) leads to a new direction for tackling the problem of PTP by using improved Ca2+ measurements in a mostly unperturbed synaptic terminal.
1Ludwig-Maximilians-Universität, Neurobiologie, Martinsried, Germany; and 2The Vollum Institute, Oregon Health and Science University, Portland, Oregon
Address for reprint requests and other correspondence: H. von Gersdorff, The Vollum Institute, Oregon Health and Science University, Portland, OR 97239 (E-mail: vongersd{at}ohsu.edu)
REFERENCES
Brager DH, Cai X, and Thompson SM. Activity-dependent activation of presynaptic protein kinase C mediates post-tetanic potentiation. Nat Neurosci 6: 551–552, 2003.[CrossRef][ISI][Medline]
Delaney KR and Tank DW. A quantitative measurement of the dependence of short-term synaptic enhancement on presynaptic residual calcium. J Neurosci 14: 5885–5902, 1994.[Abstract]
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Feng TP. Studies on the neuromuscular junction XXVI. The changes of the end-plate potential during and after prolonged stimulation. Chin J Physiol 16: 341–372, 1941.
Forsythe ID, Tsujimoto T, Barnes-Davies M, Cuttle MF, and Takahashi T. Inactivation of presynaptic calcium current contributes to synaptic depression at a fast central synapse. Neuron 20: 797–807, 1998.[CrossRef][ISI][Medline]
Geiger JR and Jonas P. Dynamic control of presynaptic Ca2+ inflow by fast-inactivating K+ channels in hippocampal mossy fiber boutons. Neuron 28: 927–939, 2000.[CrossRef][ISI][Medline]
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Korogod N, Lou X, and Schneggenburger R. Presynaptic Ca2+ requirements and developmental regulation of posttetanic potentiation at the calyx of Held. J Neurosci 25: 5127–5137, 2005.
Martin AR and Pilar G. Pre-synaptic and post-synaptic events during post-tetanic potentiation and facilitation in the avian ciliary ganglion. J Physiol 175: 17–30, 1964.
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Wojtowicz JM and Atwood HL. Correlation of presynaptic and postsynaptic events during establishment of long-term facilitation at the crayfish neuromuscular junction. J Neurophysiol 54: 220–230, 1985.
Zhong N, Beaumont V, and Zucker RS. Roles for mitochondrial and reverse mode Na+/Ca2+ exchange and the plasmalemma Ca2+ ATPase in post-tetanic potentiation at crayfish neuromuscular junctions. J Neurosci 21: 9598–9607, 2001.
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