Review Article
Relevance of presynaptic actin dynamics for synapse function and mouse behavior

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Abstract

Actin is the most abundant cytoskeletal protein in presynaptic terminals as well as in postsynaptic dendritic spines of central excitatory synapses. While the relevance of actin dynamics for postsynaptic plasticity, for instance activity-induced changes in dendritic spine morphology and synaptic glutamate receptor mobility, is well-documented, only little is known about its function and regulatory mechanisms in presynaptic terminals. Moreover, studies on presynaptic actin dynamics have often been inconsistent, suggesting that actin has diverse presynaptic functions, varying likely between specific types of excitatory synapses and/or their activity states. In this review, we will summarize and discuss the function and upstream regulatory mechanisms of the actin cytoskeleton in presynaptic terminals, focusing on excitatory synapses of the mammalian central nervous system. Due to length restrictions we will mainly concentrate on new insights into actin׳s presynaptic function that have been gained by cell biological and mouse genetic approaches since the excellent 2008 review by Cingolani and Goda.

Introduction

Neurotransmitters stored in synaptic vesicles (SVs) have to be released to allow communication between neurons which is the basis for transmitting information within neuronal circuits. Neurotransmitter release mainly takes place at a specific subcellular compartment, the presynaptic terminal, and it comprises a number of specific steps (discussed in greater detail in several other articles of this issue) all of which appear to be modulated by actin: i) transport of SVs from a storage cluster to specific release sites within the active zone (AZ), ii) SV docking to the presynaptic membrane, iii) stimulus triggered SV exocytosis, iv) SV endocytosis and v) transport of recycled SVs back to the storage cluster. No doubt that a high level of structural organization is needed to efficiently execute these different steps of the SV cycle.

Actin is highly enriched in presynaptic terminals, as demonstrated recently by combining quantitative immunoblotting of purified cerebral cortex presynaptic terminals (resealed into synaptosomes after being detached by shear forces from axons) and mass spectrometry [1]. In this study, actin׳s copy number in presynaptic terminals has been estimated to be 22,000, constituting roughly 2% of the total synaptosomal protein content. Platinum replica electron microscopy revealed that the presynaptic actin cytoskeleton consists of a branched network of actin filaments (F-actin) [2]. Hence, the presynaptic actin cytoskeleton is well-suited for providing the structural organization needed for the SV cycle. In fact, actin localizes preferentially around the synaptic vesicle cluster and is also enriched at the AZ [3], [4].

Actin shuttles between a monomeric, globular form (G-actin) and F-actin. At presynaptic terminals, assembly and disassembly of F-actin (termed actin dynamics) are temporally coordinated with synaptic activity, suggesting that F-actin is relevant for neurotransmission [3]. In fact, it is mostly the dynamics of the actin cytoskeleton that seems to be critical for presynaptic physiology rather than a net polymerization or depolymerization of filaments. At rest 25–30% of actin is in the polymerized state, and synaptic activity promotes presynaptic F-actin assembly (with a delay of 6–25 s) and the recruitment of actin to regions adjacent to the SV cluster, followed by F-actin disassembly [3]. A number of drugs are known to shift the equilibrium between G- and F-actin and thereby perturb actin dynamics (Fig. 1), such as latrunculins and cytochalasin B that promote F-actin disassembly or jasplakinolide that stabilizes F-actin [5]. By using these drugs or by genetically removing critical regulators of actin dynamics the diverse presynaptic functions of actin have been recognized, as discussed in more detail in this review.

Section snippets

Actin׳s role in vesicle pool organization and SV mobilization

SVs are organized in functionally, and to some degree also spatially, distinct pools: a readily-releasable pool (RRP) for immediate release, a recycling pool containing SVs that undergo exo-/endocytosis during sustained stimulation, and a reserve pool [6]. While the RRP is docked at the AZ, the remaining SVs are organized into a cluster within the presynaptic terminal. Actin surrounds this cluster and is linked to the SVs via synapsin [7], but is hardly found therein [3]. This localization led

A dynamic actin cytoskeleton is required for SV exocytosis

Upon arrival and attachment to the AZ, docked SVs undergo a series of reactions priming them for Ca2+-dependent exocytosis. Several lines of evidence demonstrated that actin is a major AZ constituent, and it has been suggested that F-actin forms a physical barrier that controls SV exocytosis in small synapses [8]. In such a model, inhibition of F-actin assembly would facilitate SV exocytosis, while actin stabilization would have the opposite effect. In line with this suggestion, latrunculin

Actin׳s contribution to the different modes of endocytosis

The increase in membrane area upon exocytosis has to be counterbalanced by endocytosis to keep the presynaptic architecture intact. Moreover, endocytosis retrieves SV proteins from the release sites and allows the generation of new SVs. A number of endocytic factors such as dynamin, intersectin1, syndapin, SNX-9 and N-WASP interact, either directly or indirectly, with regulators of actin dynamics [26], [27], [28], [29], [30], thereby implying actin in clathrin-mediated endocytosis (CME). While

Relevance of presynaptic actin dynamics for behavior: lessons from mouse models

In mature neurons, actin is highly enriched in dendritic spines, and postsynaptic actin dynamics is essential for morphological changes of dendritic spines. These in turn are critical for synaptic plasticity, the cellular basis for learning and memory [8]. Hence, ABPs that control actin dynamics have moved into the focus as regulators of postsynaptic plasticity, learning and memory. Indeed, inactivation of various ABPs in mice led to significant defects in learning and/or memory. As an example,

Concluding remarks

While a large number of studies have tackled the relevance of actin dynamics and upstream regulatory mechanisms for dendritic spine morphology and postsynaptic plasticity, the regulation and function of actin dynamics in presynaptic mechanisms has been studied in far fewer reports. Hence, knowledge about actin׳s presynaptic function is still very limited. While there is no doubt that actin is involved in neurotransmitter release, actin׳s contributions to the different steps of the SV cycle

Acknowledgments

We thank Dr. Walter Witke for critical reading of the manuscript. This work was supported by a Research grant of the University Medical Center Giessen and Marburg (UKGM (Grant no. 24/2014 MR)) to MBR and by grants from the DFG to TM (MA4735/1-1; SFB958/A01).

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