Review ArticleRelevance of presynaptic actin dynamics for synapse function and mouse behavior
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).
References (46)
- et al.
Actin-dependent regulation of neurotransmitter release at central synapses
Neuron
(2000) - et al.
A preferentially segregated recycling vesicle pool of limited size supports neurotransmission in native central synapses
Neuron
(2012) - et al.
Chromaffin cell cortical actin network dynamics control the size of the release-ready vesicle pool and the initial rate of exocytosis
Neuron
(1995) - et al.
ADF/cofilin: a functional node in cell biology
Trends Cell Biol.
(2010) - et al.
Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice
Neuron
(2002) - et al.
Clathrin-mediated endocytosis is the dominant mechanism of vesicle retrieval at hippocampal synapses
Neuron
(2006) - et al.
Clathrin/AP-2 mediate synaptic vesicle reformation from endosome-like vacuoles but are not essential for membrane retrieval at central synapses
Neuron
(2014) - et al.
Surfing pathogens and the lessons learned for actin polymerization
Trends Cell Biol.
(2001) - et al.
The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines
Neuron
(2008) - et al.
STED nanoscopy of actin dynamics in synapses deep inside living brain slices
Biophys. J.
(2011)
Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins
Science
Molecular architecture of synaptic actin cytoskeleton in hippocampal neurons reveals a mechanism of dendritic spine morphogenesis
Mol. Biol. Cell
Actin has a molecular scaffolding, not propulsive, role in presynaptic function
Nat. Neurosci.
Nonhomogeneous distribution of filamentous actin in the presynaptic terminals on the spinal motoneurons
J. Comp. Neurol.
The actin cytoskeleton: integrating form and function at the synapse
Ann. Rev. Neurosci.
Synaptic vesicle pools
Nat. Rev. Neurosci.
Synapsin I, an actin-binding protein regulating synaptic vesicle traffic in the nerve terminal
Adv. Second Messenger Phosphoprot. Res.
Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy
Nat. Rev. Neurosci.
Involvement of actin polymerization in vesicle recruitment at the calyx of Held synapse
J. Neurosci.
Synapsin- and actin-dependent frequency enhancement in mouse hippocampal mossy fiber synapses
Cereb. Cortex
Two modes of vesicle recycling in the rat calyx of Held
J. Neurosci.
ADF/cofilin controls synaptic actin dynamics and regulates synaptic vesicle mobilization and exocytosis
Cereb. Cortex
Actin-dependent rapid recruitment of reluctant synaptic vesicles into a fast-releasing vesicle pool
Proc. Natl. Acad. Sci. USA
Cited by (39)
Loss of the actin regulator cyclase-associated protein 1 (CAP1) modestly affects dendritic spine remodeling during synaptic plasticity
2023, European Journal of Cell BiologyRegulation of actin filament assembly and disassembly in growth cone motility and axon guidance
2023, Brain Research BulletinCitation Excerpt :A variety of studies investigated the functions of ADF and particularly of cofilin1 in the brain. Collectively, these studies identified cofilin1 as a key regulator of neuronal actin dynamics relevant during differentiation, but also in differentiated neurons (Rust et al., 2010; Rust, 2015a; Rust and Maritzen, 2015; Omotade et al., 2017), and they reported redundant functions for ADF and cofilin1, which only became apparent by the analyses of double mutant mice (Flynn et al., 2012; Rust, 2015b; Wolf et al., 2015; Zimmermann et al., 2015; Schneider et al., 2021a). Instead, first insights into the neuronal function of cofilin2 have been gained only recently (Tedeschi et al., 2019).
miR-196a enhances polymerization of neuronal microfilaments through suppressing IMP3 and upregulating IGF2 in Huntington's disease
2022, Molecular Therapy Nucleic AcidsCitation Excerpt :The actin structure composes G-actin monomers to polymerize into F-actin, known as actin filament, and forms lamellipodia, filopodia, and stress fibers to process morphogenesis.16 Especially, actin assembly is necessary for neurite outgrowth at the initial step and dendrite and dendritic spine formation at later stages,17 further facilitating synaptic functions in neurons.18 In HD, several reports have shown deficits in neuronal morphology during disease progression,13,19,20,21,22,23 suggesting that enhancement of the neuronal cytoskeleton is a potential direction to alleviate the neuropathogenesis in these neuronal diseases.
Disease association of cyclase-associated protein (CAP): Lessons from gene-targeted mice and human genetic studies
2022, European Journal of Cell BiologyCitation Excerpt :Long-term potentiation (LTP) of synaptic transmission triggers cofilin1 translocation into spines where its activity was required for the rapid sculpturing of the actin cytoskeleton and, hence, for spine morphological changes (Bosch et al., 2014). Relevance of cofilin1 for spine morphology and synaptic plasticity has been proven by the analyses of gene-targeted mice lacking either cofilin1 or cofilin1 and its close homolog ADF (Rust, 2015; Rust et al., 2010; Wolf et al., 2015), and synaptic defects in these mutants were associated with altered behavior (Goodson et al., 2012; Rust and Maritzen, 2015; Sungur et al., 2018; Zimmermann et al., 2015). The Cys32-dependent dimerization of CAP2 is necessary for LTP-induced cofilin1 translocation into spines, spine remodeling and the potentiation of synaptic transmission (Pelucchi et al., 2020b), suggesting a crucial role for CAP2 in brain function and behavior, similar to cofilin1.
Damage and repair of the axolemmal membrane: From neural development to axonal trauma and restoration
2019, Current Topics in MembranesPresynapses contain distinct actin nanostructures
2023, Journal of Cell Biology