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  • Review Article
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Lipid regulation of the synaptic vesicle cycle

Nature Reviews Neuroscience volume 6, pages 139–150 (2005)Cite this article

Key Points

  • The synaptic vesicle cycle that mediates neurotransmission is precisely regulated, both spatially and temporally, by the actions and interactions of plasma membrane and synaptic vesicle lipids and a large number of synaptic proteins. Recent studies have revealed that key aspects of the synaptic vesicle cycle are likely to be regulated by membrane lipid composition, lipid domain heterogeneity, lipid modulation and lipid-mediated signalling within synaptic membrane environments. This review focuses on newly revealed roles for lipid domain formation and modification, lipid–protein interactions and structural and metabolic forms of lipid modulation, which underlie the sustainability and fidelity of synaptic transmission.

  • Exocytosis involves vesicle targeting, docking, priming and fusion at the presynaptic active zone. Sphingolipid- and cholesterol-enriched lipid raft domains are proposed to localize important members of the SNARE protein complex required for exocytosis. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) is locally synthesized and concentrated at plasma membrane exocytic domains, interacts with multiple exocytic proteins and has crucial roles in vesicle priming and Ca2+-dependent fusion. It is likely that localized phospholipid metabolism and structural modulation also facilitate geometric restructuring of the membranes during synaptic vesicle fusion.

  • Genetic mutants and functional synaptic studies in Drosophila melanogaster provide new evidence that sphingolipid- and phospholipid-modifying enzymes regulate synaptic function. Rolling blackout (RBO), a novel lipase, is vital for neurotransmission, and functions in an activity-dependent mechanism to regulate PtdIns(4,5)P2–DAG concentrations. The ceramidase SLAB, which has a central role in sphingolipid metabolism, regulates ceramide concentrations and sphingolipid-dependent processes in a mechanism that facilitates synaptic vesicle priming and fusion during neurotransmission.

  • Genetic mutants and functional synaptic studies in D. melanogaster and Caenorhabditis elegans provide new evidence that synaptic vesicle endocytosis requires both structural and enzymatic phospholipid modulation. Clathrin-dependent synaptic vesicle endocytosis is regulated by interactions between phospholipids (e.g. PtdIns(4,5)P2), clathrin and adaptor proteins, and other key endocytic proteins. Endophilin has important roles in the structural changes in membranes that lead to vesicle fission and the localization of the PtdIns(4,5)P2 phosphatase synaptojanin, which is required for synaptic vesicle uncoating and trafficking from the plasma membrane.

  • Cholesterol–protein interactions are also likely to be important for synaptic vesicle formation and recruitment of the proper complement of vesicle proteins.

  • Lipids also have important roles in regulating synaptic vesicle trafficking between reserve and readily-releasable pools in presynaptic terminals. Activity-dependent synaptic vesicle tethering and release in vertebrate synapses is regulated by synapsin, which binds synaptic vesicle membrane lipids. Reserve pool tethering is perturbed in D. melanogaster SLAB ceramidase mutants, indicating that the synaptic sphingolipid environment modulates the tethering–release step.

  • Despite the speed and complexity of the synaptic vesicle cycle, and the lipid-dependent mechanisms mediating this cycle, new genetic mutants are beginning to allow the dissection of the structural, modulatory and signalling functions of synaptic lipids. Increased focus on this new frontier promises to expand our understanding of synaptic vesicle cycle regulation and the mechanisms controlling neurotransmission.

Abstract

Membrane vesicle cycling is orchestrated through the combined actions of proteins and lipids. At neuronal synapses, this orchestration must meet the stringent demands of speed, fidelity and sustainability of the synaptic vesicle cycle that mediates neurotransmission. Historically, the lion's share of the attention has been focused on the proteins that are involved in this cycle; but, in recent years, it has become clear that the previously unheralded plasma membrane and vesicle lipids are also key regulators of this cycle. This article reviews recent insights into the roles of lipid-modifying enzymes and lipids in the acute modulation of neurotransmission.

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Figure 1: Overview of the synaptic vesicle cycle.
Figure 2: Regulation of synaptic vesicle exocytosis by lipid raft environment.
Figure 3: Regulation of synaptic vesicle endocytosis by lipid modification and lipid–protein interactions.
Figure 4: Lipid-mediated regulation of synaptic vesicle pool tethering and mobilization.

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Acknowledgements

The authors thank R. Shattuck for assistance with the artwork, and P. De Camilli and A. Brown for insightful comments on the manuscript.

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Authors and Affiliations

  1. Department of Biological Sciences, Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, 37235-1634, Tennessee, USA

    Jeffrey Rohrbough & Kendal Broadie

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DATABASES

Entrez Gene

CaMKII

CDK5

PI3K

PI4K

PIP5K

Flybase

Cdase

endo

rbo

synj

FURTHER INFORMATION

Broadie's homepage

Glossary

SPHINGOLIPIDS

Lipid subclass including ceramides and sphingomyelin, distinguished by a long-chain sphingoid base group and fatty acid chain.

ACTIVE ZONE

An electron-dense structure in the presynaptic terminal at which secretory protein complexes are assembled for synaptic vesicle exocytosis.

PERIACTIVE ZONE

Region surrounding an active zone at which endocytic protein complexes are assembled for synaptic vesicle endocytosis.

PRESYNAPTIC RIBBON

Large, specialized active zones in photoreceptor neurons, at which arrays of synaptic vesicles are released.

RBO

(Rolling blackout). Novel lipase that is required for Drosophila melanogaster synaptic transmission.

LIPID RAFTS

Sphingolipid- and sterol-rich membrane microdomains, which are defined primarily by detergent insolubility or by the localization of protein or lipid markers thought to be targeted specifically to rafts.

SNARE

Soluble N-ethyl-maleimide-sensitive fusion protein attachment protein receptors. Highly conserved vesicle (synaptobrevin) and plasma membrane (synaxin, SNAP25) proteins mediating regulated vesicle fusion.

CERAMIDASE

A key enzyme in the sphingolipid metabolic pathway that cleaves ceramide to sphingosine.

SLAB

(Slug-a-bed). Drosophila melanogaster ceramidase that is required for normal synaptic vesicle priming/fusion and reserve pool trafficking.

BAR

(BIN/amphiphysin/Rvsp). A domain present in endophilin and amphiphysin that confers membrane binding and structural reformation activity.

FM1-43

Lipophilic fluorescent dye that is taken up by recycling vesicles, allowing visualization of cycling synaptic vesicle pools.

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Rohrbough, J., Broadie, K. Lipid regulation of the synaptic vesicle cycle. Nat Rev Neurosci 6, 139–150 (2005). https://doi.org/10.1038/nrn1608

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