Multiple overlapping processes underlying short-term synaptic enhancement
Authors: Stephen A. Fisher, Thomas M. Fischer, Thomas J. Carew
Journal: Trends in Neurosciences (1997)

Recently there have been exciting advances in understanding the mechanisms and functional roles of a form of short-term synaptic enhancement (STE) that results from an activity-dependent accumulation of Ca2+ in the presynaptic terminal. This form of STE is composed of at least four processes: fast-decaying facilitation (F1), slow-decaying facilitation (F2), augmentation (AUG) and post-tetanic potentiation (PTP). Recent results suggest that these processes can now be distinguished mechanistically by the site of their induction within the presynaptic terminal: F1 and F2 appear to be induced by a rapid, high concentration of Ca2+ at or near the site of exocytosis, whereas AUG and PTP seem to be induced by lower levels of Ca2+ with slower kinetics, possibly within the core of the terminal. STE is highly conserved across diverse species, and appears to serve as a flexible mechanism for temporal information processing in systems ranging from peripheral motor control to higher cortical integration. Recently there have been exciting advances in understanding the mechanisms and functional roles of a form of short-term synaptic enhancement (STE) that results from an activity-dependent accumulation of Ca2+ in the presynaptic terminal. This form of STE is composed of at least four processes: fast-decaying facilitation (F1), slow-decaying facilitation (F2), augmentation (AUG) and post-tetanic potentiation (PTP). Recent results suggest that these processes can now be distinguished mechanistically by the site of their induction within the presynaptic terminal: F1 and F2 appear to be induced by a rapid, high concentration of Ca2+ at or near the site of exocytosis, whereas AUG and PTP seem to be induced by lower levels of Ca2+ with slower kinetics, possibly within the core of the terminal. STE is highly conserved across diverse species, and appears to serve as a flexible mechanism for temporal information processing in systems ranging from peripheral motor control to higher cortical integration. Memory has often been described as consisting of two separate processes, short-term and long-term, that differ in their temporal properties and underlying mechanisms. Short-term memory is thought to last from less than a second to tens of minutes, whereas long-term memory can last from a few hours to a lifetime. At a mechanistic level, synaptic plasticity is hypothesized to be a neural substrate of both forms of memory, since it can exist in one of several transient, short-term forms (such as facilitation, augmentation, post-tetanic potentiation and synaptic depression) as well as sustained long-term forms (such as long-term potentiation and long-term depression). The mechanisms underlying long-term synaptic plasticity have been the subject of intense research activity in the past few years, providing many fascinating advances1Bliss T.V.P. Collingridge G.L. Nature. 1993; 361: 31-39Crossref PubMed Scopus (9604) Google Scholar, 2Linden D.J. Conner J.A. Annu. Rev. Neurosci. 1995; 18: 319-357Crossref PubMed Scopus (360) Google Scholar, 3Abraham W.C. Bear M.F. Trends Neurosci. 1996; 19: 126-130Abstract Full Text PDF PubMed Scopus (1243) Google Scholar, 4Carew T.J. Neuron. 1996; 16: 5-8Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar. However, exciting progress has also been made in the analysis of short-term synaptic plasticity. It is this work that is the primary focus of the present review. Specifically, we explore both the mechanisms and functional significance of short-term synaptic enhancement. Short-term synaptic enhancement comes in many flavors, with quite different mechanisms and apparently different behavioral functions. It can result from transient modifications in presynaptic or postsynaptic terminals and might require synaptic activity or neuromodulators for its induction. Expression might entail the modulation of membrane channels, postsynaptic receptors or intracellular ion concentrations. In this review we limit our discussion to a form of activity-dependent, short-term synaptic enhancement (STE) that has the following properties: (1) it results from a build-up of Ca2+ (or a Ca2+ complex) in the presynaptic terminal; (2) it is expressed presynaptically; (3) it does not require the modification of membrane channels; and (4) it is not dependent upon neuromodulators for induction or expression. First, we review briefly the physiological and pharmacological data demonstrating that STE is indeed a presynaptic event involving multiple Ca2+-dependent processes that appear to be highly conserved across a wide range of biological systems. Next, we consider the implications of recent data for a current biochemical model for STE. Lastly, we discuss possible functional advantages for STE in a number of diverse behavioral systems. As originally described by Feng5Feng T.P. Chin. J. Physiol. 1941; 16: 341-372Google Scholar, and by Eccles, Katz and Kuffler6Eccles J.C. Katz B. Kuffler S.W. J. Neurophysiol. 1941; 4: 362-387Google Scholar, STE was thought to reflect a single process. However, more-recent data suggest that STE consists of at least four unique components (Fig. 1)7Zengel J.E. Magleby K.L. J. Gen. Physiol. 1982; 80: 583-611Crossref PubMed Scopus (70) Google Scholar,8Magleby K.L. Zengel J.E. J. Gen. Physiol. 1982; 80: 613-638Crossref PubMed Scopus (78) Google Scholar: fast-decaying facilitation (F1), slow-decaying facilitation (F2), augmentation (AUG) and post-tetanic potentiation (PTP). These components have been differentiated by pharmacological9Zengel J.E. Magleby K.L. J. Gen. Physiol. 1980; 76: 175-211Crossref PubMed Scopus (53) Google Scholar, 10Nussinovitch I. Rahamimoff R. J. Physiol. 1988; 396: 435-455PubMed Google Scholar, 11Fischer T.M. Carew T.J. Soc. Neurosci. Abstr. 1994; 20: 1072Google Scholar, 12Goda Y. Stevens C.F. Proc. Natl. Acad. Sci. U. S. 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Neurosci. 1989; 12: 13-31Crossref PubMed Scopus (1287) Google Scholar. Following tetanic presynaptic activation the increase in synaptic efficacy has been found to decay with four time constants (τ; the time necessary to decay to 1/e of the initial magnitude following stimulation). By definition the first time constant represents F1, the second F2, then AUG and finally PTP: τF1 ∼tens of milliseconds, τF2 ∼hundreds of milliseconds, τAUG ∼thousands of milliseconds, and τPTP ≥tens of seconds. Table 1, Table 2, Table 3 illustrate the variety of time constants found in different systems, as well as the common features and differences in other properties of STE across systems. For example, the rate of increase for each component follows a similar trend to that of the decay rates: F1 always increases most rapidly, followed by F2, AUG, and lastly PTP. Furthermore almost all STE processes are linearly related to intracellular Ca2+ ([Ca2+]i) although the exact [Ca2+]i requirements are not understood fully (see below).Table 1Comparative analysis of fast-decaying facilitation (F1) and slow-decaying facilitation (F2)SystemQ10F1τF1F2τF2Accum.[Ca2+]resRefsF1F2(%)(ms)(%)(ms)Chicken––25065––––21Martin A.R. Pilar G. J. Physiol. 1964; 175: 17-30PubMed Google ScholarCat––120<25––––22Curtis D.R. Eccles J.C. J. Physiol. 1960; 150: 374-398Crossref PubMed Scopus (265) Google ScholarCrayfish––33020180410non-linear–23Zucker R.S. J. Physiol. 1974; 241: 91-110PubMed Google ScholarDrosophila–––68–400––24Mallart A. J. Physiol. (Paris). 1993; 87: 83-88Crossref PubMed Scopus (18) Google ScholarFrog3.83.817aZengel and Magleby7 fit their data better with a non-linear model [enhancement = (F1 + F2 + 1)3 – 1] where F1 = 17% and F2 = 2.7%.502.7aZengel and Magleby7 fit their data better with a non-linear model [enhancement = (F1 + F2 + 1)3 – 1] where F1 = 17% and F2 = 2.7%.380non-linear–6Eccles J.C. Katz B. Kuffler S.W. J. Neurophysiol. 1941; 4: 362-387Google Scholar,7Zengel J.E. Magleby K.L. J. Gen. Physiol. 1982; 80: 583-611Crossref PubMed Scopus (70) Google Scholar,25Mallart A. Martin A.R. J. Physiol. 1967; 193: 679-694PubMed Google Scholar,26Magleby K.L. J. Physiol. 1973; 234: 327-352PubMed Google ScholarGuinea pig–––––––linear27Wu L.G. Saggau P. J. Neurosci. 1994; 14: 645-654Crossref PubMed Google ScholarLeech––460<100––––28Stewart R.R. Adams W.B. Nicholls J.G. J. Exp. Biol. 1989; 144: 1-12PubMed Google ScholarMouse1.11.625bAmount of increase after one pulse, fitted with a linear model (enhancement = F1 + F2).3523bAmount of increase after one pulse, fitted with a linear model (enhancement = F1 + F2).163––29Gage P.W. Murphy E.C. Brain Res. 1981; 204: 327-337Crossref PubMed Scopus (7) Google ScholarRabbit–2.5140bAmount of increase after one pulse, fitted with a linear model (enhancement = F1 + F2).5985bAmount of increase after one pulse, fitted with a linear model (enhancement = F1 + F2).388––30Zengel J.E. et al.J. Gen. Physiol. 1980; 76: 213-231Crossref PubMed Scopus (65) Google ScholarRat––350100––––31Hubbard J.I. J. Physiol. 1963; 169: 641-662PubMed Google ScholarToad4.3–28040––non-linear–5Feng T.P. Chin. J. Physiol. 1941; 16: 341-372Google Scholar,7Zengel J.E. Magleby K.L. J. Gen. Physiol. 1982; 80: 583-611Crossref PubMed Scopus (70) Google Scholar,32Balnave R.J. Gage P.W. J. Physiol. 1977; 266: 435-451PubMed Google Scholar,33Balnave R.J. Gage P.W. J. Physiol. 1974; 239: 657-675PubMed Google ScholarQ10 refers to the temperature dependency of the decay of the particular component of short-term synaptic enhancement (STE). In contrast to decay, there are no reported cases in which a change in the maximum synaptic enhancement was temperature dependent6Eccles J.C. Katz B. Kuffler S.W. J. Neurophysiol. 1941; 4: 362-387Google Scholar,29Gage P.W. Murphy E.C. Brain Res. 1981; 204: 327-337Crossref PubMed Scopus (7) Google Scholar,30Zengel J.E. et al.J. Gen. Physiol. 1980; 76: 213-231Crossref PubMed Scopus (65) Google Scholar,33Balnave R.J. Gage P.W. J. Physiol. 1974; 239: 657-675PubMed Google Scholar, 34Rosenthal J. J. Physiol. 1969; 203: 121-133PubMed Google Scholar, 35Magleby K.L. J. Physiol. 1973; 234: 353-371PubMed Google Scholar, 36Magleby K.L. Zengel J.E. J. Physiol. 1976; 257: 449-470PubMed Google Scholar, except indirectly through the change in decay time. In all cases, the maximum synaptic enhancement (indicated by 'F1' and 'F2' in the table) was calculated as the normalized increase in postsynaptic potential, frequency of miniature endplate potential or quantal content immediately following presynaptic activation or pharmacological manipulation. The values reported for Q10, maximum enhancement and decay time constant (τ) are averages of the values reported by the different groups. All decay rates not computed at 20°C were adjusted with the relevant Q10 when computing the averages. In the table, Accum. refers to the build-up of enhancement with repeated stimuli. For example, a linear accumulation is one in which each additional spike adds a constant amount of enhancement to the synapse. [Ca2+]res refers to the relationship between 'residual' Ca2+ (Ca2+ in the presynaptic terminal throughout and following stimulation) and synaptic enhancement.a Zengel and Magleby7Zengel J.E. Magleby K.L. J. Gen. Physiol. 1982; 80: 583-611Crossref PubMed Scopus (70) Google Scholar fit their data better with a non-linear model [enhancement = (F1 + F2 + 1)3 – 1] where F1 = 17% and F2 = 2.7%.b Amount of increase after one pulse, fitted with a linear model (enhancement = F1 + F2). Open table in a new tab Table 2Comparative analysis of augmentation (AUG)SystemQ10AUG (%)τAUG (s)Accum.[Ca2+]resRefsAplysia––7.5––37Kretz R. Shapiro E. Kandel E.R. Proc. Natl. Acad. Sci. U. S. A. 1982; 79: 5430-5434Crossref PubMed Scopus (35) Google ScholarCrayfish––8.4–liner (Kd≤1 μm)38Delaney K.R. Tank D.W. J. Neurosci. 1994; 14: 5885-5902PubMed Google ScholarFrog3.81aIncreases 1% for first spike and 1.5n% for each additional spike, where n is the spike number.7non-linearaIncreases 1% for first spike and 1.5n% for each additional spike, where n is the spike number.liner (Kd≤1 μm)7Zengel J.E. Magleby K.L. J. Gen. Physiol. 1982; 80: 583-611Crossref PubMed Scopus (70) Google Scholar,36Magleby K.L. Zengel J.E. J. Physiol. 1976; 257: 449-470PubMed Google ScholarGuinea pig––––liner (Kd≤1 μm)39Regehr W.G. Delaney K.R. Tank D.W. J. Neurosci. 1994; 14: 523-537Crossref PubMed Google ScholarRabbit315bAmount of increase after one pulse.7.2––30Zengel J.E. et al.J. Gen. Physiol. 1980; 76: 213-231Crossref PubMed Scopus (65) Google ScholarRat––8––10Nussinovitch I. Rahamimoff R. J. Physiol. 1988; 396: 435-455PubMed Google ScholarSquid––––liner (Kd≤1 μm)40Swandulla D. et al.Neuron. 1991; 7: 915-926Abstract Full Text PDF PubMed Scopus (162) Google ScholarToadcMagleby and Zengel36 reported 'qualitatively similar' results in five toad preparations as compared to their results in the frog.3.8–7non-linear–36Magleby K.L. Zengel J.E. J. Physiol. 1976; 257: 449-470PubMed Google ScholarQ10 refers to the temperature dependency of the decay of the particular component of short-term synaptic enhancement (STE). τ is the decay time constant. Accum. refers to the build-up of enhancement with repeated stimuli. [Ca2+]res refers to the relationship between 'residual' Ca2+ and synaptic enhancement.a Increases 1% for first spike and 1.5n% for each additional spike, where n is the spike number.b Amount of increase after one pulse.c Magleby and Zengel36Magleby K.L. Zengel J.E. J. Physiol. 1976; 257: 449-470PubMed Google Scholar reported 'qualitatively similar' results in five toad preparations as compared to their results in the frog. Open table in a new tab Table 3Comparative analysis of post-tetanic potentiation (PTP)SystemQ10PTPaThe magnitude of PTP increases with frequency and duration of stimulation (but see Ref. 34). (%)τPTP (min)Accum.[Ca2+] resRefsAplysia–±290bAt some synapses in Aplysia, the amplitude of PTP in juveniles is reduced (or non-existent) when compared to the same synapse in adult animals. The value reported here was from only adult animals.±1.6PTP and τPTP increase with frequency and duration of stimulus–37Kretz R. Shapiro E. Kandel E.R. Proc. Natl. Acad. Sci. U. S. A. 1982; 79: 5430-5434Crossref PubMed Scopus (35) Google Scholar,41Schlapfer W.T. et al.Brain Res. 1976; 109: 1-20Crossref PubMed Scopus (28) Google Scholar, 42Waziri R. Kandel E.R. Frazier W.T. J. Neurophysiol. 1969; 32: 509-519PubMed Google Scholar, 43Ohmori H. J. Physiol. 1982; 322: 223-240PubMed Google Scholar, 44Conner J.A. Kretz R. Shapiro E. J. Physiol. 1986; 375: 625-642PubMed Google ScholarCat–±200±6PTP and τPTP increase with frequency and duration of stimulus–22Curtis D.R. Eccles J.C. J. Physiol. 1960; 150: 374-398Crossref PubMed Scopus (265) Google ScholarChicken–750<15––21Martin A.R. Pilar G. J. Physiol. 1964; 175: 17-30PubMed Google ScholarCrayfish––1.8–linear (Kd ≤ 1 μm)45Delaney K.R. Zucker R.S. Tank D.W. J. Neurosci. 1989; 9: 3558-3567PubMed Google Scholar,46Kamiya H. Zucker R.S. Nature. 1994; 371: 603-606Crossref PubMed Scopus (293) Google ScholarFrog2.41cIncreases 1% per spike.±0.9PTP and τPTP increase with frequency and duration of stimuluslinear7Zengel J.E. Magleby K.L. J. Gen. Physiol. 1982; 80: 583-611Crossref PubMed Scopus (70) Google Scholar,26Magleby K.L. J. Physiol. 1973; 234: 327-352PubMed Google Scholar,35Magleby K.L. J. Physiol. 1973; 234: 353-371PubMed Google Scholar,36Magleby K.L. Zengel J.E. J. Physiol. 1976; 257: 449-470PubMed Google Scholar,47Lev-Tov A. Rahamimoff R. J. Physiol. 1980; 309: 247-273PubMed Google Scholar, 48Weinreich D. J. Physiol. 1971; 212: 431-446PubMed Google Scholar, 49Magleby K.L. Zengel J.E. J. Physiol. 1975; 245: 183-208PubMed Google Scholar, 50Magleby K.L. Zengel J.E. J. Physiol. 1975; 245: 163-182Crossref PubMed Scopus (65) Google ScholarGuinea pig–––PTP increases with frequency of stimuluslinear (Kd ≤ 1 μm)39Regehr W.G. Delaney K.R. Tank D.W. J. Neurosci. 1994; 14: 523-537Crossref PubMed Google ScholarRabbit2.1±551.5PTP increases with duration of stimulus–30Zengel J.E. et al.J. Gen. Physiol. 1980; 76: 213-231Crossref PubMed Scopus (65) Google ScholarRat––±3.3PTP and τPTP increase with frequency and duration of stimulus–2Linden D.J. Conner J.A. Annu. Rev. Neurosci. 1995; 18: 319-357Crossref PubMed Scopus (360) Google Scholar,31Hubbard J.I. J. Physiol. 1963; 169: 641-662PubMed Google Scholar,51Liley A.W. North K.A.K. J. Neurophysiol. 1953; 16: 509-527PubMed Google ScholarToaddMagleby and Zengel36 reported 'qualitatively similar' results in Q10, maximum PTP and tPTP between the frog NMJ and toad NMJ.–±275<10PTP increases with frequency and duration of stimulus–5Feng T.P. Chin. J. Physiol. 1941; 16: 341-372Google ScholarQ10 refers to the temperature dependency of the decay of the particular component of short-term synaptic enhancement (STE). t is the decay time constant. Accum. refers to the build-up of enhancement with repeated stimuli. [Ca2+]res refers to the relationship between 'residual' Ca2+ and synaptic enhancement.a The magnitude of PTP increases with frequency and duration of stimulation (but see Ref. 34Rosenthal J. J. Physiol. 1969; 203: 121-133PubMed Google Scholar).b At some synapses in Aplysia, the amplitude of PTP in juveniles is reduced (or non-existent) when compared to the same synapse in adult animals. The value reported here was from only adult animals.c Increases 1% per spike.d Magleby and Zengel36Magleby K.L. Zengel J.E. J. Physiol. 1976; 257: 449-470PubMed Google Scholar reported 'qualitatively similar' results in Q10, maximum PTP and tPTP between the frog NMJ and toad NMJ. Open table in a new tab Q10 refers to the temperature dependency of the decay of the particular component of short-term synaptic enhancement (STE). In contrast to decay, there are no reported cases in which a change in the maximum synaptic enhancement was temperature dependent6Eccles J.C. Katz B. Kuffler S.W. J. Neurophysiol. 1941; 4: 362-387Google Scholar,29Gage P.W. Murphy E.C. Brain Res. 1981; 204: 327-337Crossref PubMed Scopus (7) Google Scholar,30Zengel J.E. et al.J. Gen. Physiol. 1980; 76: 213-231Crossref PubMed Scopus (65) Google Scholar,33Balnave R.J. Gage P.W. J. Physiol. 1974; 239: 657-675PubMed Google Scholar, 34Rosenthal J. J. Physiol. 1969; 203: 121-133PubMed Google Scholar, 35Magleby K.L. J. Physiol. 1973; 234: 353-371PubMed Google Scholar, 36Magleby K.L. Zengel J.E. J. Physiol. 1976; 257: 449-470PubMed Google Scholar, except indirectly through the change in decay time. In all cases, the maximum synaptic enhancement (indicated by 'F1' and 'F2' in the table) was calculated as the normalized increase in postsynaptic potential, frequency of miniature endplate potential or quantal content immediately following presynaptic activation or pharmacological manipulation. The values reported for Q10, maximum enhancement and decay time constant (τ) are averages of the values reported by the different groups. All decay rates not computed at 20°C were adjusted with the relevant Q10 when computing the averages. In the table, Accum. refers to the build-up of enhancement with repeated stimuli. For example, a linear accumulation is one in which each additional spike adds a constant amount of enhancement to the synapse. [Ca2+]res refers to the relationship between 'residual' Ca2+ (Ca2+ in the presynaptic terminal throughout and following stimulation) and synaptic enhancement. Q10 refers to the temperature dependency of the decay of the particular component of short-term synaptic enhancement (STE). τ is the decay time constant. Accum. refers to the build-up of enhancement with repeated stimuli. [Ca2+]res refers to the relationship between 'residual' Ca2+ and synaptic enhancement. Q10 refers to the temperature dependency of the decay of the particular component of short-term synaptic enhancement (STE). t is the decay time constant. Accum. refers to the build-up of enhancement with repeated stimuli. [Ca2+]res refers to the relationship between 'residual' Ca2+ and synaptic enhancement. Finally, across systems there is conclusive evidence demonstrating a presynaptic locus for STE. In particular, all systems show an increase in quantal content (m; the number of quantal packets released per spike) or frequency of spontaneous miniature endplate potentials (fMEPP) during STE, while a change in quantal amplitude (v; the postsynaptic response to a single quantal packet) has to date not been observed. A change in m with no change in v indicates that the expression of STE is presynaptic in origin (but see Refs 52Kullmann D.M. Siegelbaum S.A. Neuron. 1995; 15: 997-1002Abstract Full Text PDF PubMed Scopus (125) Google Scholar53Malinow R. Mainen Z.F. Science. 1996; 271: 1604-1606Crossref PubMed Scopus (8) Google Scholar). However, further analyses of the mechanisms underlying the change in m are not so conclusive. A change in m can be attributed to a change in the mean probability of release (p), a change in the number of releasable quanta (n; n might also represent a change in the number of transmitter release sites), or both. STE in different systems exhibits changes in p, n or both (Table 4). Thus STE is expressed presynaptically but might involve different intracellular mechanisms at different synapses. Although the site of STE appears indisputably presynaptic, this does not preclude an involvement of the postsynaptic cell during the induction phase of STE. In fact, recent evidence suggests that the induction of STE at an identified sensory neuron–motoneuron synapse in Aplysia can be inhibited by postsynaptic manipulations, such as a reduction of free Ca2+ or hyperpolarization71Cui M. Walters E.T. Soc. Neurosci. Abstr. 1994; 20: 1071Google Scholar, 72Lin X.Y. Glanzman D.L. Proc. R. Soc. London Ser. B. 1994; 255: 113-118Crossref PubMed Scopus (82) Google Scholar, 73Bao J.-X. Hawkins R.D. Soc. Neurosci. Abstr. 1995; 21: 1024Google Scholar. It will be important to examine the mechanisms of this postsynaptic modulation as it might give new insights into as yet unappreciated features of STE.Table 4Quantal analysis of short-term synaptic enhancement (STE)SystemResultRefsCatIncrease in m – increase in p54Hirst G.D.S. Redman S.J. Wong K. J. Physiol. 1981; 321: 97-109PubMed Google ScholarChickenIncrease in m; no change in v21Martin A.R. Pilar G. J. Physiol. 1964; 175: 17-30PubMed Google ScholarCrayfishIncrease in m – increase in p or n; no change in v55Dudel J. Kuffler S.W. J. Physiol. 1961; 155: 530-542PubMed Google Scholar, 56Zucker R.S. J. Physiol. 1973; 229: 787-810PubMed Google Scholar, 57Wernig A. J. Physiol. 1972; 226: 761-768PubMed Google Scholar, 58Wernig A. J. Physiol. 1972; 226: 751-759PubMed Google Scholar, 59Smith D.O. Exp. Neurol. 1983; 80: 520-528Crossref PubMed Scopus (15) Google ScholarFrogIncrease in m and fMEPP – increase in p; no change in v34Rosenthal J. J. Physiol. 1969; 203: 121-133PubMed Google Scholar,36Magleby K.L. Zengel J.E. J. Physiol. 1976; 257: 449-470PubMed Google Scholar,60Maeno T. Edwards C. J. Neurophysiol. 1969; 32: 785-792PubMed Google Scholar, 61Miledi R. Theis R. J. Physiol. 1971; 212: 245-257PubMed Google Scholar, 62Del Castillo J. Katz B. J. Physiol. 1954; 124: 574-585PubMed Google Scholar, 63Misler S. Hurlbut W.P. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 315-319Crossref PubMed Scopus (17) Google Scholar, 64Erulkar S.D. Rahamimoff R. J. Physiol. 1978; 278: 501-511PubMed Google Scholar, 65Branisteanu D.D. Miyamoto M.D. Volle R.L. J. Physiol. 1976; 254: 19-37PubMed Google ScholarLeechIncrease in m66Henderson L.P. et al.J. Physiol. 1983; 340: 347-358PubMed Google ScholarMouseIncrease in m and fMEPP67Bain A.I. Quastel D.M.J. J. Physiol. 1992; 455: 383-405PubMed Google ScholarRatIncrease in fMEPP – increase in p or n; no change in v51Liley A.W. North K.A.K. J. Neurophysiol. 1953; 16: 509-527PubMed Google Scholar,68Liley A.W. J. Physiol. 1956; 133: 571-587PubMed Google Scholar, 69Quilliam J.P. Tamarind D.L. J. Physiol. 1973; 235: 317-331PubMed Google Scholar, 70Bennett M.R. Florin T. J. Physiol. 1974; 238: 93-107PubMed Google ScholarToadIncrease in m; no change in v36Magleby K.L. Zengel J.E. J. Physiol. 1976; 257: 449-470PubMed Google Scholar (but see also Ref. 33Balnave R.J. Gage P.W. J. Physiol. 1974; 239: 657-675PubMed Google Scholar)Abbreviations: fMEPP, frequency of miniature endplate potentials; m, number of quantal packets released per spike; n, number of releasable quanta; p, mean probability of release; v, presynaptic response to a single quantal packet. Open table in a new tab Abbreviations: fMEPP, frequency of miniature endplate potentials; m, number of quantal packets released per spike; n, number of releasable quanta; p, mean probability of release; v, presynaptic response to a single quantal packet. Recently there have been many exciting advances in our understanding of the mechanisms underlying STE. Similarly, new and expanded models of STE have emerged. Here we will consider the impact of recent data on the long-standing residual Ca2+ hypothesis. In addition, we will explore some alternative models of STE. In a landmark paper, Katz and Miledi74Katz B. Miledi R. J. Physiol. 1968; 195: 481-492Crossref PubMed Scopus (921) Google Scholar proposed that facilitation at the neuromuscular junction (NMJ) is due to a residue of [Ca2+]i that enters the presynaptic terminal during nerve stimulation. To explore this hypothesis they used a paired-pulse paradigm and a 'Ca2+-free' Ringer solution: they first elicited transmitter release at the frog NMJ with a 'conditioning' pulse to the motor nerve, followed 100 ms later with a 'test' pulse, again to the motor nerve. The amount of facilitation of the endplate potential was measured as a decrease in the number of failures in synaptic transmission. With this paradigm they were able to add extracellular Ca2+ ([Ca2+]o) to the NMJ at selected times to explore its effects upon facilitation. They found that the absence of [Ca2+]o during the conditioning pulse would virtually abolish facilitation, even though [Ca2+]o was present during the test pulse. These data illustrate that [Ca2+]o plays an important role in the induction of facilitation at the NMJ. Furthermore, it is apparent that Ca2+ interacts with the conditioning pulse in some fashion to enhance the transmission of a later pulse. Based on these results, Katz and Miledi74Katz B. Miledi R. J. Physiol. 1968; 195: 481-492Crossref PubMed Scopus (921) Google Scholar proposed the 'residual Ca2+ hypothesis' in which they postulated that some amount of Ca2+, which enters the nerve terminal during the conditioning pulse, persists until the test pulse, thereby increasing [Ca2+]i during the test pulse and facilitating synaptic transmission (see also Ref. 75Rahamimoff R. Yaari Y. J. Physiol. 1973; 228: 241-257PubMed Google Scholar). Given the amount of facilitation they reported and the timecourse of their experiment (100 ms pulse interval), Katz and Miledi74Katz B. Miledi R. J. Physiol. 1968; 195: 481-492Crossref PubMed Scopus (921) Google Scholar were probably studying both F1 and F2. Recent data continue to implicate residual Ca2+ not only in F1 and F2 (Ref. 46Kamiya H. Zucker R.S. Nature. 1994; 371: 603-606Crossref PubMed Scopus (293) Google Scholar) but also in AUG and PTP (Refs 37Kretz R. Shapiro E. Kandel E.R. Proc. Natl. Acad. Sci. U. S. 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