Modes and mechanisms of synaptic vesicle recycling

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Highlights

  • Exocytosed SV membrane and proteins have to be recycled to sustain neurotransmission.

  • SV membrane retrieval and SV reformation appear to be separable processes.

  • The exact modes and mechanisms for SV recycling remain under debate.

  • SV membranes can be retrieved by clathrin-dependent and clathrin-independent mechanisms.

  • SV reformation via clathrin occurs at the plasma membrane or endosome-like vacuoles.

Neurotransmission requires the recycling of synaptic vesicles (SVs) to replenish the SV pool, clear release sites, and maintain presynaptic integrity. In spite of decades of research the modes and mechanisms of SV recycling remain controversial. The identification of clathrin-independent modes of SV recycling such as ultrafast endocytosis has added to the debate. Accumulating evidence further suggests that SV membrane retrieval and the reformation of functional SVs are separable processes. This may allow synapses to rapidly restore membrane surface area over a wide range of stimulations followed by slow reformation of release-competent SVs. One of the future challenges will be to pinpoint the exact mechanisms that link SV recycling modes to synaptic activity patterns at different synapses.

Introduction

Neuronal communication depends on the regulated release of neurotransmitters from synaptic vesicles (SVs) by calcium-triggered exocytic fusion at specialized presynaptic release sites within so-called active zones (AZs) [1•, 2•]. To prevent expansion of the presynaptic plasma membrane and a corresponding loss of lateral membrane tension (i.e. tension within the plane of the membrane) SV exocytosis is followed by compensatory endocytic membrane retrieval. Moreover, SVs of correct size and composition have to be reformed in order to sustain neurotransmission. Finally, recent data suggest that endocytosis is also required to clear release sites [3] from previously exocytosed material (i.e. SV proteins, SNARE complexes, etc.) [4, 5, 6•, 7•], which may be rate-limiting for exocytosis at fast-firing synapses [3]. As synapses differ vastly with respect to their SV pool sizes and firing pattern, it is conceivable that synapses have evolved specific separate mechanisms to maintain membrane homeostasis and to replenish the readily releasable SV pool. The exact nature and molecular components of the various modes of SV recycling and the underlying mechanisms remain a matter of debate.

Section snippets

Proposed modes of SV recycling

Pioneering studies based on electron microscopy (EM) analysis of stimulated nerve-muscle preparations suggested that SV membranes are recycled by clathrin-mediated endocytosis (CME) from cisternal structures located away from AZs [8]. Using the same preparation, but a different stimulation paradigm Ceccarelli et al. [9] proposed an alternative clathrin-independent rapid mode of SV recycling by kiss-and-run exocytosis/endocytosis (K&R) of SVs at AZs involving a transient fusion pore. While

Mechanisms and components of presynaptic membrane retrieval and SV reformation

Key distinctive features of K&R, UFE, ADBE, and CME are their differential dependence on clathrin and its associated factors (i.e. AP-2, AP180) as well as the speed and fidelity at which SV membrane and protein retrieval and SV reformation occur (Figure 1, Table 1). In K&R, UFE, and ADBE membrane internalization post-fusion is independent of clathrin and its main recruitment factor AP-2, while membrane retrieval via CME strictly depends on clathrin/AP-2 and dynamin in essentially all cell types

Sorting of SV proteins and other presynaptic cargo

Sustained rapid neurotransmission not only depends on release site clearance and the restoration of lateral membrane tension post-exocytic fusion, but also requires that SVs of correct size and composition are reformed. Imaging analysis indeed suggests that SV protein copy numbers are tightly controlled [47], presumably at multiple levels. High-resolution time-lapse imaging has revealed that newly exocytosed SV proteins rapidly disperse post-fusion until confined within the presynaptic bouton

Modulation of SV recycling

A number of endocytic proteins, the so-called dephosphins (i.e. dynamin 1 [57], synaptojanin 1, AP180, amphiphysin 1), have long been known to be functionally regulated via activity-dependent dephosphorylation by calcineurin, a serine/threonine protein phosphatase with a key role in SV recycling [58]. Recent studies have uncovered additional mechanisms, which regulate SV recycling at different types of synapses. For example, LRRK2, a kinase mutated in Parkinson's disease, modulates presynaptic

Conclusion and perspectives

In spite of decades of studies on the modes and mechanisms of SV recycling and the rich molecular information gathered in recent years, many key questions remain controversial. Cumulating evidence suggests that the mechanisms of presynaptic membrane retrieval and reformation of functional SVs are at least partially separable with distinct phenotypes of genetic manipulations of endocytic proteins on the kinetics of SV protein retrieval and the fidelity of SV protein sorting and SV reformation [1•

Conflict of interest statement

None of the authors of this work declare any conflict of interest.

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

Our own research was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) [SFB958/A01; SFB958/A07; HA 2686/8-1 and MA4735/1-1] and the Neurocure Cluster of Excellence (DFG-Exc-257).

References (66)

  • H.F. Renard et al.

    Endophilin-A2 functions in membrane scission in clathrin-independent endocytosis

    Nature

    (2015)
  • P.Y. Pan et al.

    Vesicular glutamate transporter 1 orchestrates recruitment of other synaptic vesicle cargo proteins during synaptic vesicle recycling

    J Biol Chem

    (2015)
  • V. Uytterhoeven et al.

    Loss of skywalker reveals synaptic endosomes as sorting stations for synaptic vesicle proteins

    Cell

    (2011)
  • X.S. Wu et al.

    Calcineurin is universally involved in vesicle endocytosis at neuronal and nonneuronal secretory cells

    Cell Rep

    (2014)
  • H. Chen et al.

    Rapid Ca2+-dependent decrease of protein ubiquitination at synapses

    Proc Natl Acad Sci U S A

    (2003)
  • S.O. Rizzoli

    Synaptic vesicle recycling: steps and principles

    EMBO J

    (2014)
  • E. Neher

    What is rate-limiting during sustained synaptic activity: vesicle supply or the availability of release sites

    Front Synaptic Neurosci

    (2010)
  • V. Haucke et al.

    Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

    Nat Rev Neurosci

    (2011)
  • N. Hosoi et al.

    Calcium dependence of exo- and endocytotic coupling at a glutamatergic synapse

    Neuron

    (2009)
  • Y. Hua et al.

    Blocking endocytosis enhances short-term synaptic depression under conditions of normal availability of vesicles

    Neuron

    (2013)
  • B. Ceccarelli et al.

    Depletion of vesicles from frog neuromuscular junctions by prolonged tetanic stimulation

    J Cell Biol

    (1972)
  • T. Fernandez-Alfonso et al.

    Synaptic vesicles interchange their membrane proteins with a large surface reservoir during recycling

    Neuron

    (2006)
  • N. Gimber et al.

    Diffusional spread and confinement of newly exocytosed synaptic vesicle proteins

    Nat Commun

    (2015)
  • Y. Hua et al.

    A readily retrievable pool of synaptic vesicles

    Nat Neurosci

    (2011)
  • M. Wienisch et al.

    Vesicular proteins exocytosed and subsequently retrieved by compensatory endocytosis are nonidentical

    Nat Neurosci

    (2006)
  • S. Watanabe et al.

    Ultrafast endocytosis at Caenorhabditis elegans neuromuscular junctions

    Elife

    (2013)
  • S. Watanabe et al.

    Ultrafast endocytosis at mouse hippocampal synapses

    Nature

    (2013)
  • S. Watanabe et al.

    Clathrin regenerates synaptic vesicles from endosomes

    Nature

    (2014)
  • N.H. Revelo et al.

    A new probe for super-resolution imaging of membranes elucidates trafficking pathways

    J Cell Biol

    (2014)
  • N.L. Kononenko et al.

    Compromised fidelity of endocytic synaptic vesicle protein sorting in the absence of stonin 2

    Proc Natl Acad Sci U S A

    (2013)
  • S.J. Koo et al.

    Vesicular synaptobrevin/VAMP2 levels guarded by AP180 control efficient neurotransmission

    Neuron

    (2015)
  • P.A. Vanlandingham et al.

    AP180 couples protein retrieval to clathrin-mediated endocytosis of synaptic vesicles

    Traffic

    (2014)
  • B. Zhang et al.

    Synaptic vesicle size and number are regulated by a clathrin adaptor protein required for endocytosis

    Neuron

    (1998)
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