Role of Ca2+ channels in short-term synaptic plasticity

Role of Ca2+ channels in short-term synaptic plasticityJianhua Xu, Liming He and Ling-Gang Wu

Repetitive nerve activity induces various forms of short-term

synaptic plasticity that have important computational roles in

neuronal networks. Several forms of short-term plasticity are

caused largely by changes in transmitter release, but the

mechanisms that underlie these changes in the release process

have been difficult to address. Recent studies of a giant

synapse — the calyx of Held — have shed new light on this

issue. Recordings of Ca2+ currents or Ca2+ concentrations at

nerve terminals reveal that regulation of presynaptic Ca2+

channels has a significant role in three important forms of short-

term plasticity: short-term depression, facilitation and post-

tetanic potentiation.

Addresses

National Institute of Neurological Disorders and Stroke, Bethesda, MD

20892, USA

Corresponding author: Wu, Ling-Gang ([email protected])

Current Opinion in Neurobiology 2007, 17:352–359

This review comes from a themed issue on

Signalling mechanisms

Edited by Stuart Cull-Candy and Ruediger Klein

Available online 26th April 2007

0959-4388/$ – see front matter

Published by Elsevier Ltd.

DOI 10.1016/j.conb.2007.04.005

IntroductionNeurons fire repetitively at frequencies that range from

less than one to hundreds of hertz for various periods of

time [1,2]. Repetitive firing can temporarily change

synaptic strength, resulting in various forms of short-term

plasticity, such as facilitation (which lasts for less than a

few seconds), depression (which lasts for a few to tens of

seconds) and post-tetanic potentiation (which can last for

minutes). These forms of short-term plasticity are crucial

for neuronal network computations [3]. Therefore, it is

important to understand how short-term plasticity is

generated.

Accumulated evidence suggests that the origin of short-

term plasticity is largely presynaptic, although postsyn-

aptic mechanisms are involved in certain conditions [4–6].

It remains not well understood how transmitter release is

regulated to achieve short-term plasticity. Although trans-

mitter release is triggered by Ca2+ influx through voltage-

gated Ca2+ channels, regulation of Ca2+ channels has not

generally been considered as a major mechanism in short-


term plasticity. Recent studies at a large mammalian

central synapse, the calyx of Held in the rat (or mouse)

medial nucleus of the trapezoid body, indicate that regu-

lation of voltage-gated Ca2+ channels is important in

mediating short-term plasticity. This review focuses on

these studies of the calyx of Held synapse.

The relationship between transmitter releaseand the presynaptic Ca2+ currentWhen an action potential arrives at the nerve terminal,

voltage-activated Ca2+ channels open to allow Ca2+ influx

that triggers transmitter release. About four decades ago,

transmitter release at the neuromuscular junction was

found to be proportional to the extracellular Ca2+ con-

centration raised to power of three or four [7,8]. A similar

power relation was subsequently observed between trans-

mitter release and the presynaptic Ca2+ current (ICa) or

the presynaptic intracellular Ca2+ concentration at many

synapses, such as the squid giant synapse [9], hippo-

campal CA3–CA1 synapses [10], the goldfish retinal

bipolar synapse [11] and the calyx of Held synapse

(Figure 1a) [12–15,16��]. According to this nonlinear

(e.g. fourth power) relationship, a small change in the

Ca2+ influx (e.g. 90% of control) is amplified to a large

change in transmitter release (e.g. 66%). Thus, modu-

lation of Ca2+ influx or Ca2+ channels provides an efficient

and economic way to modulate transmitter release. Ca2+

channels can be regulated by various factors, such as

voltage, Ca2+ and various neurotransmitters and neuro-

modulators [17–19]. However, regulation of Ca2+ chan-

nels had not been considered the dominant mechanism

mediating short-term plasticity. Ca2+ currents are difficult

to record at most synapses, where nerve terminals are too

small for voltage-clamp recordings. The ability to perform

simultaneous presynaptic and postsynaptic voltage-clamp

recordings at the calyx of Held synapse [20,21] made it

possible to study quantitatively the contribution of Ca2+

channels to short-term plasticity at this synapse.

The calyx of Held synapse is a glutamatergic synapse

located in the auditory brainstem of the rat or mouse [5].

In rats aged ten days old or younger, the calyx of Held

contains three types of voltage-gated Ca2+ channel — P/Q-

type, N-type and R-type — whereas older calyces contain

only P/Q-type channels [13,22–24]. In mouse, P/Q-type

and N-type channels are present in immature calyces, but

only P/Q-type channels are present in more mature calyces

[25,26�]. P/Q-type channels are more efficient than N-type

and R-type channels in controlling transmitter release,

probably because they are physically located closer to

the release site than other types [13]. Similarly, P/Q-type

channels are more efficient in controlling release than

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Role of Ca2+ channels in short-term synaptic plasticity Xu, He and Wu 353

Figure 1

Ca2+/calmodulin-mediated Ca2+ current inactivation is a primary source of short-term depression at the calyx of Held synapse. (a) (i) The presynaptic

Ca2+ current (ICa) and the excitatory postsynaptic current (EPSC) induced by 1 ms depolarization from a holding potential of –80 mV to +5 mV

(black), +2 mV (blue), �2 mV (green) or �4 mV (red) applied to the calyx. The interval between each depolarization is >30 s. (ii) The relationship

between the normalized EPSC amplitude and the ICa charge (six synapses) was fitted with a linear regression line (slope = 3.6) in a double logarithmic

scale. (b) The decrease in the presynaptic ICa accounts for the EPSC depression. (i) Sampled ICa and EPSC induced by ten action-potential-equivalent

stimuli (AP-e; 1 ms depolarization from �80 to +2 mV) at 10 Hz, followed by an AP-e at an interval to test for the recovery. (ii,iii) ICa charge (open circles)

and the EPSC amplitude (black triangles) during (ii) and after (iii) 10 AP-e at 10 Hz. The measured ICa charge was also raised to a power of

3.6 (red). Data were normalized to the first response. (c) ICa in response to a pair of AP-e at an interval of 200 ms in calyces dialyzed with control

pipette solution (i), the Ca2+ chelator BAPTA (10 mM; ii) or a specific calmodulin inhibitor, the myosin light chain kinase (MLCK) peptide (20 mM; iii).

Note that BAPTA and MLCK largely relieved paired-pulse depression of ICa. Adapted, with permission, from [16��].

N-type and/or R-type channels at cerebellar synapses [27]

and neuromuscular junctions [28,29]. It is suggested that as

the calyx matures during development, there is a reduction

in the number of Ca2+ channels that control transmitter

release at single release sites [30]. The physical distance

between Ca2+ channels and the release site or the endogen-

ous Ca2+ buffer capacity also decreases, which increases the

efficiency of Ca2+ channels in controlling release [30].

Thus, developmental changes and the types of Ca2+ chan-

nel can affect the efficiency of Ca2+ channels in regulating

transmitter release.

Short-term depressionRepetitive stimulation causes short-term depression

(STD) of synaptic transmission at many synapses [1,4,5].

At the calyx of Held synapse, STD is more prominent in


immature than in mature animals [31], so the majority of

studies have been performed in immature calyces

(Figure 1b). STD during repetitive firing at �10 Hz is

caused by a presynaptic mechanism [32]. As the frequency

of firing is increased, postsynaptic AMPA receptor desen-

sitization [33,34] also contributes to STD [35,36]; however,

significant depression remains after relieving postsynaptic

receptor desensitization, indicating that the presynaptic

mechanism is a dominant source of STD [35,36].

What is the presynaptic mechanism that underlies STD?

Depletion of a readily releasable pool of vesicles (RRP) is

the most popular hypothesis [4], and this hypothesis has

been confirmed at the calyx after a 10 ms presynaptic

depolarization that depletes the RRP [37–39]. However,

depletion of the RRP is not the only mechanism that


354 Signalling mechanisms

underlies STD after a 10 ms presynaptic depolarization. A

decrease in the release probability downstream of the

presynaptic ICa and a decrease in presynaptic ICa itself

also contribute to STD after a 10 ms depolarization [37].

Which of these presynaptic mechanisms mediate STD

induced by action potential trains? Recent studies

indicate that although all of these mechanisms can con-

tribute to STD [16��,38,40,41], a decrease in the presyn-

aptic ICa is the dominant mechanism during repetitive

action-potential-like stimulation at frequencies ranging

from <2 Hz to 30 Hz in 7–10-day-old rats [16��].

Inactivation of the presynaptic ICa was first found after a

prolonged (e.g. 10 s) train of action potentials at 100 Hz

[40]. The decrease in the ICa largely accounts for STD

after the prolonged train of stimulation. However, this

mechanism was discounted, because an atypically intense

stimulus was used to generate it, and STD during 100 Hz

stimulation was not caused by ICa inactivation [40]. A

recent study has shown inactivation of ICa for a wide range

of stimulation conditions that are typically used to induce

STD [16��]. The stimulus includes 2–20 action-potential-

equivalent stimuli (AP-e) at 0.2–100 Hz. Except during

100 Hz stimulation, ICa is decreased during and after

stimulation. Because release is proportional to ICa raised

to a power of 3.6 (Figure 1a), the decreased ICa raised to a

power of 3.6 gives an estimate of the contribution of ICa

inactivation to STD (Figure 1b). The estimated contri-

bution matches closely to the measured STD during and

after trains of AP-e, particularly �30 Hz (Figure 1b).

Furthermore, STD, including paired-pulse depression,

is largely relieved when the ICa decrease is compensated

by a change in the voltage command [16��] or when ICa is

replaced with photolysis of a caged Ca2+ compound that

evokes release without activating Ca2+ channels [42].

These results suggest that ICa decrease, but not depletion

of the RRP, is the major cause of STD during 2–20 AP-e

at�30 Hz and after 2–20 AP-e at frequencies from<2 Hz

to 100 Hz.

ICa inactivation is mainly due to inactivation of P/Q-type

Ca2+ channels [16��,40]. The decrease of ICa during

stimulation is largely relieved by the Ca2+ buffer bis-

(o-aminophenoxy)-ethane-N,N,N’,N’-tetraacetic acid

(BAPTA; Figure 1c) or by replacing the extracellular

Ca2+ with Ba2+ or Na+, suggesting that Ca2+ induces

ICa inactivation [16��,40]. Calmodulin, a Ca2+-binding

protein, might mediate Ca2+-induced ICa inactivation,

because three calmodulin inhibitors — including a 17

amino acid myosin light chain kinase peptide (Figure 1c),

a calmodulin-binding domain peptide and an organic

calmodulin inhibitor calmidazolium — significantly

reduce ICa inactivation [16��].

Why is depletion of the RRP not the major mechanism

during 2–20 AP-e at �30 Hz? This is because each AP-e

depletes only �5% of the RRP [16��] and, even after a


complete depletion, more than half of the RRP is replen-

ished within�200–300 ms [16��,37,38]. Only during AP-e

trains at �100 Hz is depletion the dominant mechanism

[16��]. In addition, during prolonged high-frequency

(�100 Hz) firing, activation of presynaptic adenosine

A1 receptors and group III metabotropic glutamate recep-

tors can contribute to STD [43,44] by inhibition of

ICa [22,45].

Short-term facilitationShort-term synaptic facilitation (STF) is generally

thought to be caused by an elevated intracellular Ca2+

concentration that remains from the previous stimulus,

termed residual Ca2+ [4,46,47]. The main evidence for

this is the ability of Ca2+ chelators to attenuate both

residual Ca2+ and STF [4]. It is hypothesized that residual

Ca2+ enhances the release probability by binding to a Ca2+

sensor different from the one that mediates evoked ex-

ocytosis [4].

At the calyx of Held, STF is not observed in normal

extracellular solution because STD is overwhelming [5].

However, during repetitive action-potential-like depolar-

izing pulses at 100–200 Hz, ICa is facilitated by a maxi-

mum of 10–20% (Figure 2a), owing to an increased rate of

activation [48,49]. In this situation, only P/Q-type Ca2+

channels are facilitated [25,26�]. Facilitation of ICa is

attenuated by loading the calyx with Ca2+ chelators or

by replacing the extracellular Ca2+ with Ba2+ (Figure 2a),

suggesting that residual Ca2+ mediates ICa facilitation

[48,49]. Loading the calyx with neuronal Ca2+ sensor 1

(NCS1), a neuron-specific high-affinity Ca2+-binding

protein, increases ICa induced by a brief depolarization

by accelerating the activation time of ICa in a Ca2+-de-

pendent manner, and largely occludes ICa facilitation

(Figure 2b) [50]. Furthermore, loading the calyx with a

C-terminal peptide of NCS1 greatly reduces ICa facili-

tation [50]. These results suggest that Ca2+ facilitates ICa

by binding to NCS1 [50].

Given that STD overwhelms STF at the calyx-type

synapse in normal extracellular solution, the role of ICa

facilitation might be to counteract mechanisms that cause

STD. When postsynaptic AMPA receptor desensitization

is relieved by application of competitive AMPA receptor

blockers such as kynurenic acid or g-D-glutamylglycine

(g-DGG), the excitatory postsynaptic current (EPSC) is

initially facilitated during a train of action potentials or

action-potential-like depolarizing pulses at 50–100 Hz

[16��,35,51]. The facilitated EPSCs during the first four

stimuli are of approximately the same size as the EPSC

predicted from ICa facilitation (raising the facilitated ICa

to a power of 3.6; Figure 2c), suggesting that ICa facili-

tation contributes significantly to STF [16��]. In mice that

have P/Q-type Ca2+ channels knocked out, both ICa

facilitation and the EPSC facilitation are absent

(Figure 2d) [25,26�]. This correlation provides strong



Figure 2

ICa facilitation induced by Ca2+ and neuronal Ca2+ sensor 1 (NCS1) significantly contributes to short-term facilitation. (a) The ICa facilitation (lower)

induced by a train of action potential waveforms (upper) at 100 Hz in control conditions (i) was largely abolished when the calyx was loaded with 10 mM

BAPTA (ii). Adapted, with permission, from [48]. (b) Superimposed ICa traces evoked by paired pulses at different intervals from a calyx in control

conditions (i) and a calyx loaded with exogenous NCS1 (20 mM; ii). Note that NCS1 largely occludes ICa facilitation. Adapted, with permission,

from [50]. (c) (i) Sampled ICa and EPSC induced by a train of AP-e at 100 Hz. (ii) ICa charge (open circles) and EPSC amplitude (black triangles)

during a train of AP-e at 100 Hz (n = 13). Only the first eight stimuli are shown. The measured ICa charge was also raised to a power of 3.6 (red).

Kynurenate (1 mM) and cyclothiazide (100 mM) were added in the bath solution. The error bars indicate standard error of the mean. Adapted, with

permission, from [16��]. (d) (i) Superimposed ICa traces recorded from mouse calyces by paired 2 ms depolarizing pulses with intervals of

5–45 ms. ICa facilitation was observed in the wild-type mouse (WT) but not in a P/Q-type channel knockout mouse (KO). (ii) Paired-pulse facilitation of

the EPSC was observed in the wild-type but not in the P/Q-type knockout mouse, suggesting that ICa facilitation causes paired-pulse facilitation.

Adapted, with permission, from [25]. (e) Superimposed samples of presynaptic ICa and EPSC evoked by paired pulses with various intervals (Dt) at a

calyx of Held synapse. The bath solution contained cyclothiazide to relieve AMPA receptor desensitization. The results in this study suggest that ICa

facilitation is insufficient to fully account for paired-pulse facilitation. Adapted, with permission, from [51].

evidence that ICa facilitation is a major source of STF

[25,26�].

However, not all studies agree quantitatively with this

conclusion. In one study [51], the EPSC was facilitated to

�220% of control, whereas ICa was facilitated to only

�110% of control during paired-pulse stimulation

(Figure 2e) [51]. ICa facilitation could account for only

about one-third of paired-pulse facilitation [51]. A supra-

linear summation of residual Ca2+ with the Ca2+ influx,

probably caused by saturation of the Ca2+ buffer, was

considered to be the major mechanism underlying paired-

pulse facilitation [51]. This conclusion is consistent with a

study of the mossy fiber–CA3 synapse [52], in which


saturation of an endogenous Ca2+ buffer (calbindin) in

the nerve terminal contributed to STF. However, the

�120% increase in paired-pulse facilitation of the EPSC

reported in [51] is much larger than the�0–40% increases

reported in other studies (e.g. [16��,35], and a report of no

apparent change [36] from the same laboratory as [51]).

The reason for this apparent discrepancy is unclear. It

seems likely that the contribution of ICa facilitation to

STF varies depending on the degree of STF, and thus the

condition of the synapse. Nevertheless, all studies agree

that ICa facilitation contributes to STF.

At other synapses, the block of STF by Ca2+ chelators such

as glycol-bis(2-aminoethylether)-N,N,N’,N’-tetraacetic



acid (EGTA) is often interpreted as activation of a Ca2+

sensor that enhances the release probability [4,46]. The

findings at the calyx of Held provide an alternative expla-

nation: that Ca2+ chelators attenuate STF by diminishing

Ca2+-induced ICa facilitation. In addition, Ca2+ chelators

might block STF by minimizing saturation of Ca2+ buffers

in the nerve terminal [51,52].

Post-tetanic potentiationPost-tetanic potentiation (PTP) is also caused by residual

Ca2+ at the nerve terminal [4,46]. It is hypothesized that

residual Ca2+ enhances the release probability by acting

on a molecular target different from the Ca2+ sensor that

mediates evoked exocytosis [4]. At the calyx of Held,

PTP can be induced by intense afferent fiber stimulation,

such as 4 s stimulation at 100 Hz (Figure 3a) [53�] or

5 min stimulation at 20 Hz [54�]. Similar to other synapses

[4], at the calyx of Held the Ca2+ chelator EGTA attenu-

ates the increase of residual Ca2+ and thus PTP

(Figure 3a) [53�,54�]. Knowing that residual Ca2+ can

facilitate ICa in the calyx (Figure 2), it is natural to ask

whether EGTA attenuates PTP by blocking Ca2+-

induced ICa facilitation. To address this question, ICa

was recorded from the calyx in the whole-cell configur-

ation; however, in this configuration PTP was absent,

probably owing to washout of molecules that mediate

PTP [53�,54�]. Thus, instead of whole-cell recordings of

ICa, fluorescent Ca2+ indicator dyes were loaded into the

calyx via a whole-cell patch pipette for a few minutes,

followed by pipette removal to maintain PTP [55��]. The

Ca2+ influx in the calyx evoked by a single action poten-

tial was found to increase by�15% at the peak of the PTP

(Figure 3b). This increase gradually returned to the base-

line with a time course similar to that of PTP. Based

on the highly non-linear relationship between the EPSC

and the presynaptic Ca2+ influx, the increase in the

Figure 3

A Ca2+-induced increase in presynaptic Ca2+ influx contributes significantly

stimulation (applied at time 0) at 100 Hz for 1 s (gray) or 4 s (black) induced

membrane-permeant Ca2+ chelator EGTA-AM (ii). Adapted, with permission

evoked by an action potential before PTP (black) and during PTP (gray). PTP w

of ten individual traces. The calyx was preloaded with 200 mM Fluo-4, a fluo

fluorescence increase (DFAP) divided by the basal fluorescence level (F0). Ad


presynaptic Ca2+ influx largely accounts for the PTP

[55��]. The increased Ca2+ influx was probably caused

by Ca2+-induced ICa facilitation [55��]; however, action

potential broadening could not be ruled out. In addition,

an increase in the RRP size might contribute up to 30% of

the PTP induced by 5 min stimulation at 20 Hz [55��],although this phenomenon is not observed when PTP is

induced by 4 s stimulation at 100 Hz [53�].

Conclusions and future directionsRegulation of presynaptic Ca2+ channels is traditionally

not considered a major mechanism underlying synaptic

plasticity. Recent studies at the giant calyx of Held

synapse reveal that regulation of Ca2+ channels, particu-

larly those of the P/Q-type, in nerve terminals contributes

significantly to STD and STF. During STD, ICa is

inactivated by a Ca2+–calmodulin-mediated pathway,

whereas during STF, ICa is facilitated by Ca2+ that binds

to NCS1. A Ca2+-induced increase of Ca2+ influx, possibly

via facilitation of ICa, also contributes significantly to the

generation of PTP. These findings suggest that Ca2+-

induced regulation of presynaptic Ca2+ channels is a

common mechanism to generate short-term plasticity at

the calyx of Held synapse.

It is generally thought that STF and PTP are caused by

residual Ca2+, which enhances the release probability by

binding to a Ca2+ sensor different from the one that

mediates evoked release, whereas STD is largely caused

by depletion of the RRP. The finding of Ca2+-induced ICa

facilitation at the calyx provides an additional mechanism

by which residual Ca2+ can enhance the release prob-

ability during STF. The finding of Ca2+-induced ICa

inactivation at the calyx provides another major mechan-

ism by which STD can be achieved. It is therefore

important to determine whether the findings at the calyx

to the generation of post-tetanic potentiation (PTP). (a) Afferent fiber

PTP of the EPSC in control conditions (i) but not after application of the

, from [53�]. (b) The presynaptic Ca2+ transients (i) and the EPSCs (ii)

as induced by 20 min fiber stimulation at 20 Hz. Each trace is an average

rescent Ca2+ indicator. Fluorescence transients (%) are shown as the

apted, with permission, from [55��].



of Held apply to other synapses. In addition, we think it is

important to address the following three questions at the

calyx of Held in the near future. First, why does Ca2+

induce ICa facilitation during STF, but ICa inactivation

during STD? Is the choice between upregulation or

downregulation of ICa a balanced output of two separate

Ca2+-dependent pathways? Second, given that calmodu-

lin can mediate Ca2+-induced ICa facilitation and inacti-

vation [56,57], why is ICa inactivation but not facilitation

mediated by calmodulin at the calyx of Held? Third, is

the increase of the presynaptic Ca2+ influx during PTP

mediated by Ca2+-induced ICa facilitation?

UpdateIn addition to ICa inactivation and depletion of the RRP, a

decrease in the release probability, caused by a mechan-

ism independent of ICa inactivation, contributes to STD

induced by prolonged depolarization [37], and probably

contributes to STD during high-frequency trains of

action-potential-like stimulation [16��,41]. Two recent

studies shed light on how the decrease in the release

probability is achieved at the calyx of Held [58,59]. One

suggests that after depletion of the RRP, newly recruited

vesicles are likely to be at a site further away from the

Ca2+ channel cluster [58]; the other study suggests that

the stimulation-induced increase of the intracellular Ca2+

concentration decreases the sensitivity of readily relea-

sable vesicles to Ca2+ [59].

As discussed in the main text, two studies do not agree on

whether an increase in the RRP size contributes to PTP at

the calyx of Held [53�,55��]. This controversy is resolved

by a recent study, which shows a significant increase of

the RRP size >60 s, but not 20 s, after a train of action

potential stimulation at 100 Hz for 4 s [60]. Thus, the lack

of an increase in the RRP size, as previously reported at

20 s after 4 s stimulation at 100 Hz [53�], is due to

measurement of the RRP size at an earlier time. Further-

more, the new study suggests that at physiological tem-

peratures, the increase in the RRP size lasts longer than

the increase in the release probability (which is caused by

an increase of the Ca2+ influx), and is a more significant

mechanism underlying PTP [60].

AcknowledgementWe thank Mr Benjamin McNeil and Dr David Nees for the comments onthe manuscript. This work was supported by the National Institute ofNeurological Disorders and Stroke Intramural Research Program.

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The results regarding Ca2+ current facilitation are similar to those in [25]but published one year later. The functional significance of N-type and P/Q-type Ca2+ channels in controlling transmitter release were compared atthe calyx of Held synapse in wild-type mice and in P/Q-type channelknockout mice. Both short-term facilitation of the EPSC and facilitation ofthe presynaptic Ca2+ currents were absent in P/Q-type knockout mice,suggesting a significant contribution of P/Q-type Ca2+ channels in short-term facilitation.

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28. Urbano FJ, Piedras-Renteria ES, Jun K, Shin HS, Uchitel OD,Tsien RW: Altered properties of quantal neurotransmitterrelease at endplates of mice lacking P/Q-type Ca2+ channels.Proc Natl Acad Sci USA 2003, 100:3491-3496.

29. Nudler S, Piriz J, Urbano FJ, Rosato-Siri MD, Renteria ES,Uchitel OD: Ca2+ channels and synaptic transmission at theadult, neonatal, and P/Q-type deficient neuromuscularjunction. Ann N Y Acad Sci 2003, 998:11-17.

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relevance for short-term plasticity. Biophys J 2003,84:1563-1579.

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43. Wong AY, Billups B, Johnston J, Evans RJ, Forsythe ID:Endogenous activation of adenosine A1 receptors,but not P2X receptors, during high-frequency synaptictransmission at the calyx of Held. J Neurophysiol 2006,95:3336-3342.

44. Billups B, Graham BP, Wong AY, Forsythe ID: Unmaskinggroup III metabotropic glutamate autoreceptor functionat excitatory synapses in the rat CNS. J Physiol 2005,565:885-896.

45. Kimura M, Saitoh N, Takahashi T: Adenosine A(1) receptor-mediated presynaptic inhibition at the calyx of Held ofimmature rats. J Physiol 2003, 553:415-426.

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47. Dittman JS, Kreitzer AC, Regehr WG: Interplay betweenfacilitation, depression, and residual calcium at threepresynaptic terminals. J Neurosci 2000, 20:1374-1385.

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51. Felmy F, Neher E, Schneggenburger R: Probing the intracellularcalcium sensitivity of transmitter release during synapticfacilitation. Neuron 2003, 37:801-811.

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53.�

Korogod N, Lou X, Schneggenburger R: Presynaptic Ca2+

requirements and developmental regulation of posttetanicpotentiation at the calyx of Held. J Neurosci 2005,25:5127-5137.

This study shows that brief trains of 100 Hz fiber stimulation induced post-tetanic potentiation (PTP) of transmitter release at the calyx of Held thatlasted for�1 min. PTP was more prominent in immature rats than in maturerats. Bath application of the membrane-permeable Ca2+ chelator EGTA-AM suppressed PTP. Presynaptic Ca2+ imaging showed that the intracel-lular Ca2+ concentration was increased by 40–120 nM at the peak of PTP,and this ’residual’ Ca2+ decayed in parallel with PTP. These results suggestthat residual Ca2+ in the nerve terminal is responsible for the generation ofPTP. The readily releasable pool size did not change during PTP, suggest-ing that PTP is caused by an increased release probability.

54.�

Habets RL, Borst JG: Post-tetanic potentiation in the rat calyxof Held synapse. J Physiol 2005, 564:173-187.

This study and [53�] were the first to report PTP at the calyx of Heldsynapse. The amplitude of the EPSC was increased more than twofold bya 5 min 20 Hz fiber stimulation, and it returned to the control value within afew minutes. Such PTP was accompanied by a clear increase in thefrequency, but not in the amplitude, of spontaneous EPSCs. The size ofthe readily releasable pool of vesicles was increased by �30%; PTP wasaccompanied by an increase in the presynaptic Ca2+ concentration to�210 nM, and the decay of the PTP matched the decay of this increase.When the decay of the Ca2+ transient was shortened by dialysing theterminal with EGTA, the PTP decay sped up in parallel. These resultssuggest that PTP is mostly due to an increase of residual Ca2+ thatenhances the release probability.

55.��

Habets RL, Borst JG: An increase in calcium influx contributesto post-tetanic potentiation at the rat calyx of Held synapse.J Neurophysiol 2006, 96:2868-2876.

The authors improved the imaging resolution of the Ca2+ signal evoked byan action potential in the calyx of Held. This enabled them to identify an�15% increase in the presynaptic Ca2+ transient during PTP. Theincrease of the presynaptic Ca2+ transient largely accounts for PTP of



the EPSC, suggesting that PTP is caused mainly by an increase inpresynaptic Ca2+ influx.

56. DeMaria CD, Soong TW, Alseikhan BA, Alvania RS,Yue DT: Calmodulin bifurcates the local Ca2+ signalthat modulates P/Q-type Ca2+ channels. Nature 2001,411:484-489.

57. Liang H, DeMaria CD, Erickson MG, Mori MX, Alseikhan BA,Yue DT: Unified mechanisms of Ca2+ regulation across theCa2+ channel family. Neuron 2003, 39:951-960.


58. Wadel K, Neher E, Sakaba T: The coupling between synapticvesicles and Ca2+ channels determines fast neurotransmitterrelease. Neuron 2007, 53:563-575.

59. Wolfel M, LouX,Schneggenburger R:A mechanism intrinsic to thevesicle fusion machinery determines fast and slow transmitterrelease at a large CNS synapse. J Neurosci 2007, 27:3198-3210.

60. Habets RL, Borst JG: Dynamics of the readily-releasable poolduring post-tetanic potentiation in the rat calyx of Heldsynapse. J Physiol 2007, in press.


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Role of Ca2+ channels in short-term synaptic plasticity