Elsevier

Cell Calcium

Volume 37, Issue 5, May 2005, Pages 489-495
Cell Calcium

Presynaptic Ca2+ dynamics, Ca2+ buffers and synaptic efficacy

https://doi.org/10.1016/j.ceca.2005.01.003Get rights and content

Abstract

In synapses neurotransmitter release is triggered by elevation of Ca2+ concentration at a Ca2+ sensor of the release machinery. The Ca2+ concentration at the release site at the given time point is determined by Ca2+ dynamics within presynaptic terminal. It depends on a source of Ca2+ (usually voltage-gated Ca2+ channels), diffusional distance between the source of Ca2+ and the Ca2+ sensor and Ca2+ buffering by endogenous Ca2+ buffers. In many synapses transmitter release can be enhanced (facilitated) during repetitive activity of neurons. The main source of facilitation is activity-dependent increase of Ca2+ concentration at the release site. Several mechanisms of facilitation have been proposed, namely, accumulation of residual Ca2+, multi-site (X receptor) mechanism and partial Ca2+ buffer saturation mechanism. In this review we discuss theoretical and experimental evidence in favor of one or the other of proposed mechanisms.

Introduction

In chemical synapses action potentials trigger neurotransmitter release from a presynaptic nerve terminal through exocytosis of neurotransmitter filled synaptic vesicles at the active zone. Membrane depolarisation induced by action potential (AP) opens voltage-gated calcium channels that leads to the influx of calcium into the cell. Calcium binds to a Ca2+ sensor of the release machinery and triggers the release of neurotransmitters from synaptic vesicles with a latency of a few hundred microseconds [1], [2]. Transmitter release is a complex process that involves several steps of protein-protein interaction (see, for review, [3]). The underlying mechanisms are not still well understood. However, it is very well established that Ca2+ ions trigger transmitter release and that efficacy of the transmitter release depends on Ca2+ concentration at the release site, that in turn, depends on the distance between calcium channels and the Ca2+ sensor as well as on the properties of endogenous Ca2+ buffers [4].

Endogenous calcium buffers such as parvalbumin, calretinin and calbindin are widely expressed in many neurons throughout the central nervous system, but they were generally used to classify different types of interneurons. Whether or not endogenous calcium buffers (ECB) can interfere with synaptic release was mainly the matter of theoretical debates [4]. However, shaping of the persynaptic calcium dynamics ECB should have a strong impact on both initial release probability (p) and short-lasting modification of synaptic gain.

The efficacy of synaptic transmission in neuronal circuits is not constant but varies with the rate of AP firing in the presynaptic neurons. When a train or pair of presynaptic APs occur within short time interval (<1 s), the amplitudes of successively evoked postsynaptic potentials (PSPs) either increase (facilitate) or decrease (depress) in their mean amplitude. These two types of the synaptic short-term plasticity (STP) estimated as paired-pulse facilitation (PPF) and paired-pulse depression (PPD), depend on the identity of neurons that form the connection, on the extracellular Ca2+ concentration and on the time interval between presynaptic action potentials [1], [5], [6], [7]. While the main presynaptic mechanism of PPD is thought to be a reduction of p due to vesicle depletion and, therefore, paired pulse ratio (PPR) in this case does not reflect the presynaptic calcium dynamic, in facilitating terminals, enhancement of the release rate is a product of an increasing intraterminal Ca2+ concentration. However, in order to understand role of ECB in facilitation one needs to figure out determinants of facilitation itself. The mechanisms underlying PPF have been investigated in a variety of preparations, such as neuromuscular junctions, organotypic cell cultures and acute brain slices [8], [9], [10], [11], [12].

Three different models have been suggested to explain PPF. Katz and Miledi [1] have proposed so called residual calcium hypothesis. According to their hypothesis, facilitation is caused by the slow decay of the calcium transient following each AP, the residual Ca2+ then adds to the Ca2+ elevation resulting from subsequent APs, increasing the probability of transmitter release. Later it has been demonstrated that this mechanism underlies PPF at neocortical excitatory connections [12]. Alternatively, it has been suggested that facilitation involves an additional high-affinity Ca2+ binding site (X receptor) with slow unbinding kinetics, which operates cooperatively with the main release sensor [10]. This model assumes that Ca2+ rapidly binds to the additional site during the first AP and remains bound by the time of the second AP, thus increasing the amount of neurotransmitter release in response to the second AP. The third hypothesis explains facilitation as a result of progressive and local saturation of the fast endogenous Ca2+ buffers in the terminal during a train of APs, assuming that this would gradually increase the Ca2+ concentration at the release sensor [13]. Recently, this mechanism has been shown to operate at a number of synapses such as in cortical calbindin-containing inhibitory and excitatory terminals [14] as well as at giant Calix of Held synapses [15]. In this review, we want to discuss these mechanisms stressing on how Ca2+ buffers with different kinetics of Ca2+ binding may influence PPF.

Section snippets

Facilitation due to accumulation of free Ca2+

The basic statement of residual calcium hypothesis is that after each AP calcium transient does not collapse instantly, but declines double exponentially so that the slow component persists over hundreds of milliseconds. The latter was confirmed by direct calcium measurements from presynaptic boutons [16]. The slow decaying Ca2+ can add to a new Ca2+ influx triggered by subsequent AP and consequently promote release (Fig. 1). However, in order to do that residual Ca2+ concentration should be

Facilitation due to Ca2+ buffer saturation

Facilitation due to accumulation of free Ca2+ is possible only when Ca2+ buffers capacity in the presynaptic terminals of the projecting neurons is very low, so that Ca2+ in the terminal could stay in unbound form for tens of milliseconds. However, a number of facilitating connections are established by presynaptic neurons, in particular interneurons, which express different Ca2+ binding proteins, such as calbindin, calretinin and parvalbumin that may act as Ca2+ buffers. For instance, mossy

Concluding remarks

We discussed two different mechanisms of PPF, namely facilitation due to accumulation of free Ca2+ and due to partial and local Ca2+ buffer saturation, with respect to possible contribution of endogenous Ca2+ buffers to STP. In the view of discussed experimental studies the suggested model of facilitation that involves an additional high-affinity Ca2+ binding site with slow unbinding kinetics (X receptor) operating cooperatively with the main release sensor can be considered as the model for

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