Short-term forms of presynaptic plasticity

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Synapses exhibit several forms of short-term plasticity that play a multitude of computational roles. Short-term depression suppresses neurotransmitter release for hundreds of milliseconds to tens of seconds; facilitation and post-tetanic potentiation lead to synaptic enhancement lasting hundreds of milliseconds to minutes. Recent advances have provided insight into the mechanisms underlying these forms of plasticity. Vesicle depletion, as well as inactivation of both release sites and calcium channels, contribute to synaptic depression. Mechanisms of short-term enhancement include calcium channel facilitation, local depletion of calcium buffers, increases in the probability of release downstream of calcium influx, altered vesicle pool properties, and increases in quantal size. Moreover, there is a growing appreciation of the heterogeneity of vesicles and release sites and how they can contribute to use-dependent plasticity.

Highlights

► Synapses exhibit several forms of short-term plasticity. ► Depression is due to vesicle depletion as well as release site and calcium channel inactivation. ► Residual calcium, calcium channel facilitation, and buffer saturation underlie facilitation. ► PTP results from an increase in release probability, but other mechanisms have also been proposed. ► Heterogenous vesicular properties complicate interpretation of PTP mechanisms.

Introduction

A ubiquitous property of synapses is the ability to keep track of the history of activity. This history is encoded in various forms of activity-dependent plasticity that shape synaptic output and may form the basis of learning and memory. Short-term plasticity lasts from tens of milliseconds to several minutes and is thought to underlie information processing. It can lead to bidirectional changes in synaptic strength, which can be reduced for hundreds of milliseconds to seconds (depression), or it can be enhanced for hundreds of milliseconds to seconds (facilitation), to tens of seconds to minutes (augmentation and post-tetanic potentiation, PTP). Net plasticity at synapses reflects an interaction between multiple forms of plasticity. Here we will discuss recent advances in clarifying the mechanisms underlying these different forms of plasticity.

Section snippets

Synaptic depression

At many synapses, repeated stimuli delivered at short time intervals lead to a transient decrease in synaptic strength. Here, we will focus on presynaptic mechanisms that contribute to a decrease in neurotransmitter release [1]. Several factors can account for reduced release, including but not limited to vesicle depletion, inactivation of release sites, and decreased presynaptic calcium influx (Figure 1a).

Depletion of the readily releasable pool

There are typically hundreds of vesicles associated with one active zone, but usually fewer than 5% of these vesicles are readily released with repeated stimulation [2]. The number of vesicles released by an action potential depends on the size of this readily releasable pool (RRP) of vesicles, and on the probability of release of these vesicles. Because the number of vesicles in the RRP is limiting, if an action potential releases a large fraction of the RRP, subsequent stimuli delivered

Inactivation of release sites

According to a second model of synaptic depression, fusion of a vesicle at a release site can inhibit subsequent fusion events at that site even if the RRP is not depleted [12•, 13]. This proposed site inactivation lasts for seconds following exocytosis and could reflect the time it takes to clear vesicular membrane proteins, which get incorporated into the plasma membrane upon vesicle fusion, from the release site [12]. A recent study suggests a surprising role for endocytosis in limiting the

Reduction in calcium influx

At many synapses including some neocortical synapses, axo-axonic synapses of the Mauthner neuron in the goldfish, and vestibular afferent synapses, the properties of depression are inconsistent with RRP depletion [15, 16, 17]. Activity-dependent decreases in calcium influx could account for depression at these synapses. Because of the steep dependence of neurotransmitter release on calcium [12], even small activity-dependent changes in calcium entry can lead to significant presynaptic

Molecular determinants of depression and recovery from depression

Pharmacological or genetic manipulation of many proteins can influence depression [1, 23, 24, 25]. This is not surprising considering that the initial probability of release, presynaptic calcium signaling, endocytosis, the size of vesicle pools, and replenishment of these pools can all influence depression and recovery from depression [4, 13, 26, 27]. Consequently it is often difficult to interpret a change in the extent of depression. This is illustrated by considering the dramatic alleviation

Facilitation

For most synapses with a low initial probability of release, repeated stimulation at short time intervals leads to a transient increase in transmitter release probability [34]. This short-lived synaptic facilitation depends on presynaptic calcium. Several mechanisms have been proposed to account for facilitation (Figure 1b).

Residual calcium

One proposed mechanism for facilitation involves residual calcium (Cares) that persists in the presynaptic terminal following synaptic activation [1]. At the calyx of Held, linear summation of Cares (hundreds of nanomolar) with the high local calcium levels at a release site evoked by an action potential (Calocal of tens to hundreds of micromolar) will not lead to sufficient enhancement of synaptic transmission [35]. It has therefore been hypothesized that Cares increases the probability of

Saturation of endogenous calcium buffers

Another potential mechanism for facilitation involves calcium-binding proteins within presynaptic terminals that normally intercept calcium ions between calcium channels and release sites, thus reducing the initial probability of release [38, 39]. If the first stimulus leads to calcium occupying some of these calcium-binding proteins, then more calcium will reach the release site in response to the second stimulus, and the probability of release will be elevated. This mechanism of facilitation

Facilitation of calcium currents

An increase in presynaptic calcium influx could increase the probability of release and contribute to facilitation. It has been known for some time that calcium currents can be enhanced in a use-dependent manner [41, 42]. Moreover, calcium-sensitive proteins such as calmodulin have previously been implicated in use-dependent increases in presynaptic calcium entry [20]. A crucial link among these two sets of observations and facilitation was made when it was found that mutating P-type calcium

Augmentation and post-tetanic potentiation

Augmentation and PTP are two closely related forms of enhancement that are observed following sustained, high-frequency synaptic activation [1]. PTP lasts for tens of seconds to minutes, and becomes longer lasting when the stimulus frequency and duration are increased. Augmentation is induced with less prolonged stimulation and lasts for 5–10 s. Different synapses exhibit considerable differences in the frequency and number of stimuli needed to induce augmentation and PTP, and the distinction

Conclusions

In the past decade significant advances have been made in clarifying the mechanisms responsible for short-term plasticity. Depletion of readily releasable vesicles, inactivation of release sites, and inactivation of presynaptic calcium channels can all contribute to synaptic depression. Local saturation of calcium buffers, facilitation of presynaptic calcium channels, and Cares-dependent processes can lead to synaptic facilitation. Increased quantal size, Cares-dependent increases in the

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Miklos Antal, Aaron Best, John Crowley, Court Hull, Skyler Jackman, Michael Myoga, Todd Pressler, and Monica Thanawala for comments on a previous version of the manuscript. This work was supported by NIH grant R37 NS032405 to WGR.

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