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Synaptic vesicle pools

Key Points

  • All synaptic vesicles are similar in terms of their ultrastructure and biochemistry, but for several decades investigators have proposed that there are 'pools' with distinct functional properties. These pools have been given a bewildering array of names, but this review proposes that each vesicle can be assigned to one of three pools: the readily releasable pool (RRP), the recycling pool and the reserve pool.

  • Vesicle pools have been investigated in many systems, but five preparations have been characterized most thoroughly — Drosophila larval neuromuscular junction (NMJ), frog NMJ, neonatal rodent cultured hippocampal neurons, neonatal rodent calyx of held neurons and goldfish retinal bipolar cells.

  • The RRP is defined as the synaptic vesicles that are immediately available on neural stimulation. These vesicles are generally thought to be docked to the presynaptic active zone and primed for release, although docked vesicles are not necessarily immediately releasable.

  • The recycling pool is the pool of vesicles that maintain release on moderate stimulation. Physiological frequencies of stimulation cause it to recycle continuously, and it is refilled by newly recycled vesicles.

  • The reserve pool is a depot of synaptic vesicles from which release is triggered only during intense stimulation. These vesicles constitute the majority of vesicles in most presynaptic terminals, and it is possible that they are seldom or never recruited during physiological activity.

  • Traditionally, vesicle pools have been depicted as being morphologically segregated into distinct clusters, and the RRP must, by definition, lie at or close to the presynaptic membrane. However, recent evidence indicates that, at least in some preparations at least, vesicles in the recycling and reserve pools are intermixed to a considerable degree.

  • It has been proposed that synapsin holds together the vesicles in the reserve pool, and that some kind of 'cage', perhaps consisting of actin, prevents the dispersal of recycling vesicles. However, it is also possible to visualize a model in which all vesicles are equally mobile, but only the recycling pool can exocytose efficiently on interaction with the active zone.

  • It is proposed that recycling pool vesicles are generally retrieved through endocytosis directly from the plasma membrane, whereas reserve pool release is followed by bulk endocytosis. A fraction of the vesicles in mammalian systems might recycle through an ultrafast 'kiss-and-run' pathway, in which vesicles fuse transiently to the plasma membrane and reform by the closure of a fusion pore.

Abstract

Communication between cells reaches its highest degree of specialization at chemical synapses. Some synapses talk in a 'whisper'; others 'shout'. The 'louder' the synapse, the more synaptic vesicles are needed to maintain effective transmission, ranging from a few hundred (whisperers) to nearly a million (shouters). These vesicles reside in different 'pools', which have been given a bewildering array of names. In this review, we focus on five tissue preparations in which synaptic vesicle pools have been identified and thoroughly characterized. We argue that, in each preparation, each vesicle can be assigned to one of three distinct pools.

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Figure 1: Three vesicle pools.
Figure 2: Typical images from the Drosophila larval neuromuscular junction preparation.
Figure 3: Typical images from the frog neuromuscular junction preparation.
Figure 4: Typical images from the rat cultured hippocampal preparation.
Figure 5: Typical images from the rat calyx of Held preparation.
Figure 6: Typical images from the dissociated goldfish retinal bipolar cell preparation.
Figure 7: Topology, recycling and mobilization of vesicle pools.
Figure 8: Readily releasable pool and recycling pool vesicles can recycle selectively.

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Acknowledgements

We thank H. Kuromi (Maebashi), L. Lagnado (Cambridge), E. Neher (Göttingen) and R. Tsien (Palo Alto) for their helpful comments on the manuscript. W.J.B. is supported by research grants from the National Institutes of Health and the Muscular Dystrophy Association.

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Glossary

CALYX OF HELD SYNAPSE

A giant nerve terminal in the auditory brainstem, it has a pivotal role in the circuitry that is responsible for locating high-frequency sounds.

ACTIVE ZONE

A portion of the presynaptic membrane that faces the postsynaptic density across the synaptic cleft. It constitutes the site of synaptic vesicle clustering, docking and transmitter release.

FLASH PHOTOLYSIS

Cells are dialysed with a caged calcium compound (such as nitrophenyl-EGTA); ultraviolet flashes are then used to break the cage to release calcium. In this way, the technique stimulates exocytosis independently of calcium entry from the extracellular space.

FLUORESCENCE RECOVERY AFTER PHOTOBLEACHING

(FRAP). A method used to measure the lateral diffusion of elements. It requires tagging of the molecule of interest with a fluorescent marker, photobleaching of the label with a pulse of laser light and a subsequent measure of the rate of fluorescence recovery into the bleached area as other labelled molecules move into it.

SNARE PROTEINS

A family of membrane-tethered coiled-coil proteins that are required for membrane fusion in exocytosis (such as during neurotransmitter release) and other membrane transport events. When trans-SNARE complexes are formed between vesicle SNAREs and target-membrane SNAREs, they pull the two membranes together, presumably causing them to fuse.

CLATHRIN

A vital structural component of coated vesicles that are implicated in protein transport. Clathrin heavy and light chains form a triskelion, the main building element of clathrin coats.

DOMINANT NEGATIVE

A mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

PATCH-CLAMP CAPACITANCE TECHNIQUE

A glass pipette is sealed against the membrane and an alternating voltage signal applied. The induced current is recorded and used to calculate the membrane capacitance. The capacitance of the membrane is proportional to its surface, and so gives a measure of the amount of exocytosis or endocytosis taking place.

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Rizzoli, S., Betz, W. Synaptic vesicle pools. Nat Rev Neurosci 6, 57–69 (2005). https://doi.org/10.1038/nrn1583

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