Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

Key Points

  • Nervous system function crucially depends on synaptic vesicle exocytosis and endocytosis at defined areas within the nerve terminal. Exocytosis preferentially occurs at defined release sites within the active zone, whereas synaptic vesicle membranes are retrieved largely from the surrounding periactive zone.

  • Release may be limited by a given fixed number of release sites that need to be cleared prior to the next presynaptic fusion event. This release site clearance is likely to be of physiological importance, for example, during short-term plasticity.

  • Evidence from the calyx of Held synapse shows that interference with endocytic protein function causes defects in short-term plasticity, and hence, in release site clearance. This indicates that synaptic vesicle exocytosis and endocytosis are tightly coupled.

  • Multidomain proteins of the active and surrounding periactive zones are potential scaffolds that couple exocytic fusion to the clearance of release sites.

  • Possible models regarding the mechanism by which release sites are cleared may involve lateral diffusion or removal of clustered synaptic vesicle proteins and/or dynamin-mediated membrane remodelling.

Abstract

Mechanisms that ensure robust long-term performance of synaptic transmission over a wide range of activity are crucial for the integrity of neuronal networks, for processing sensory information and for the ability to learn and store memories. Recent experiments have revealed that such robust performance requires a tight coupling between exocytic vesicle fusion at defined release sites and endocytic retrieval of synaptic vesicle membranes. Distinct presynaptic scaffolding proteins are essential for fulfilling this requirement, providing either ultrastructural coordination or acting as signalling hubs.

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Figure 1: An overview of the synaptic vesicle cycle.
Figure 2: Hypothetical timing of synaptic vesicle exocytosis–endocytosis.
Figure 3: Scaffolds in exocytic–endocytic coupling.
Figure 4: Hypothetical models for exocytic–endocytic coupling.

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Acknowledgements

Work in the authors' laboratories was supported by grants from the German Research Foundation (Deutsche Forschungsgemeinschaft; DFG).

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Correspondence to Volker Haucke.

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Glossary

Active zone

(Often abbreviated to AZ.) An area in the presynaptic compartment that is specialized for rapid exocytosis and contains multidomain proteins acting as scaffolds in the organization of release sites.

Periactive zone

An array of endocytic proteins that surround the active zone and into which synaptic vesicle membranes are recycled following exocytosis.

Release site

Docking sites for synaptic vesicles within active zones that can be empty and accessible for a vesicle, occupied and ready for fusion, or empty and inaccessible.

Cytoplasmic matrix of the active zone

(Often abbreviated to CAZ.) An electron-dense largely detergent-resistant matrix comprising multidomain proteins that may form release sites for exocytosis.

Super-resolution light microscopic techniques

Forms of light microscopic technique that achieve spatial resolution of 50 to 100 nm, beyond the limit set by diffraction; they include stimulated emission depletion microscopy (STED), photoactivated localization microscopy (PALM) and stochastic optical reconstruction microscopy (STORM).

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Haucke, V., Neher, E. & Sigrist, S. Protein scaffolds in the coupling of synaptic exocytosis and endocytosis. Nat Rev Neurosci 12, 127–138 (2011). https://doi.org/10.1038/nrn2948

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