Trends in Cell Biology
Volume 16, Issue 8, August 2006, Pages 413-420
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Review
The efficiency of the synaptic vesicle cycle at central nervous system synapses

https://doi.org/10.1016/j.tcb.2006.06.007Get rights and content

Presynaptic nerve terminals rely heavily on membrane traffic to maintain efficient neurotransmission between cells. It is often assumed that, as neurons can fire action potentials at high frequency, the cell biological machinery for vesicle cycling must be highly specialized. Here, we examine the demands that are placed on the recycling machinery in three model systems used to characterize vertebrate vesicle recycling – small hippocampal synapses, calyx-type brainstem synapses, and ribbon-type sensory synapses – and the molecular pathways thought to underlie certain aspects of the vesicle cycle.

Introduction

Information flow in the brain is mediated by chemical synapses, which transduce electrical signals within neurons into chemical signals between cells – through the release of neurotransmitters from vesicles within the pre-synaptic terminal – and back into electrical signals once again. Synapses are thus crucial modulators of signaling in the brain. Although propagation of electrical signals in the neuronal axon relies on properties of ion channels in the cell membrane that work in the millisecond time range, sustained function of chemical synapses requires membrane traffic to and from the plasma membrane, which works on longer time scales. Membrane trafficking of synaptic vesicles (SVs) coordinates the exocytosis of neurotransmitter and the endocytosis of vesicular components. Following exocytosis, SVs are retrieved from the plasma membrane and refilled with neurotransmitter locally within nerve terminals; they can be used for multiple rounds of release [1]. Although trafficking of new SVs from the cell body to the synapse probably takes several hours [2], local vesicle turnover takes only minutes or even seconds 3, 4, 5, 6. Recycling is thus a key feature of SV function that helps avoid profound failure in synaptic transmission that would occur if local vesicle stores deplete [7].

The number of recycling vesicles and the speed with which they fuse and are retrieved from the plasma membrane impose limits on the time periods and frequencies with which information can be transmitted by exocytosis during repetitive stimulation. Understanding which steps in the vesicle cycle are rate-limiting under different operational conditions should help identify potential substrates for modulation of synaptic efficacy. Many membrane trafficking molecules identified in non-neuronal cells seem to have parallel functions at the synapse, although in general it is still unclear what molecular specializations have taken place to provide kinetic proficiency to the SV cycle.

Here, we review what is known about the kinetics of two steps in the vesicle cycle, exocytosis and endocytosis, in vertebrate central nervous system (CNS) synapses and put this in the context of known physiological demands. We focus on three widely used model systems (Figure 1). Firstly, neurons of the mammalian hippocampus have several axonal branches that connect with multiple postsynaptic neurons through hundreds of small synapses (diameter <1 μm, ten times smaller than the other systems covered here; Figure 1a). Each of these small synapses usually contains a single synaptic contact. Fluorescent probes have been widely used to visualize and quantify recycling synaptic vesicles in this system. A major advantage of this model is that measurements can be done at single release sites.

Secondly, neurons of the auditory pathway in the brainstem make ‘giant synapses’ (called calyx of Held or calyceal synapses) onto the cell body of a single postsynaptic neuron through hundreds of synaptic contacts (Figure 1b). The large presynaptic terminal of these neurons (with a diameter of >10 μm) is accessible to patch clamp recordings, and thus capacitance measurements can be done to quantify changes in the plasma membrane surface, reflecting the integrated balance of exocytosis and endocytosis from the hundreds of release sites. An advantage of this technique is that sub-millisecond events can be detected both pre- and post-synaptically. Anatomically, this giant synapse looks like multiple small synapses that have been specialized to transmit information to a single postsynaptic neuron, thus apparently gaining in transmission fidelity at the expense of having a single postsynaptic partner.

Thirdly, bipolar cells of the retina and hair cells of the inner ear have synapses characterized by the presence of ribbons, electron-dense protrusions that are decorated with synaptic vesicles (Figure 1c). These neurons are also amenable to capacitance measurements owing to their large presynaptic terminals containing ∼50 synaptic contacts, which link to multiple branches corresponding to one or a few post-synaptic fibers. To understand the cell-biological basis of how these synapses might differ in their performance, we will examine the number of recycling vesicles as well as the speeds of exocytosis and endocytosis for the three types of synapse.

Section snippets

Releasable vesicle pools

During a train of intense neuronal activity, SVs in the presynaptic terminal continually fuse with the plasma membrane. The number of vesicles available for exocytosis (i.e. the size of the pool of releasable vesicles) sets a limit on the ability of a given synapse to relay information for a given time period. Larger pools of releasable vesicles thus allow synapses to function during longer periods of activity without relying on recycling.

Rates of exocytosis

The fusion of vesicles with the plasma membrane is a common end-point in the secretory pathway of all cells, both for secreting extracellular signals and for delivering important transmembrane proteins to the cell surface. At synapses this biological pathway has been specialized in ways that enable it to be controlled precisely by electrical activity and maintain high rates of secretion that specifically tap the pools of releasable vesicles mentioned earlier.

Rates of endocytosis

The finite size of the releasable pools of vesicles, coupled with the potential demand for high rates of exocytosis, necessitates a close coupling between exocytosis and endocytosis at nerve terminals. How this coupling is achieved remains an area of intense investigation, and it is unclear whether the pathways for endocytosis at nerve terminals are specializations of the pathways that exist in all cells or a separate mechanistic class of membrane traffic (Box 1). As a first step, recent

Limits on transmission imposed by endocytosis and final considerations

During sustained stimulation, as vesicles in the releasable pool undergo fusion, if the speed of endocytosis is too slow with respect to exocytosis it will increasingly affect the fidelity of transmission, because vesicles will accumulate on the cell surface, gradually limiting the capacity of the synapse to relay information.

Concluding remarks

Although information transfer during synaptic transmission can take place on a millisecond time scale, the underlying kinetics of the synaptic vesicle cycle take place over many seconds. Among the different vertebrate systems in which CNS vesicle recycling has been studied directly, the demands of information transfer have been met by different arrangements of release sites.

In the ramified networks of the hippocampus, the rates of exocytosis seem to be sufficient to cope with stimulation

Acknowledgements

We thank Takayuki Yamashita for discussions of work done in the calyx of Held.

Glossary

Synaptic contact
the sites of intimate contact between regions of pre- and post-synaptic plasma membranes, which appear electron-dense in ultrastructural electron micrographs.
Presynaptic density
the region of a synapse (also called active zone) where vesicles fuse and receptors cluster; it also defines the release site.
Release site
the region of the presynaptic terminal that surrounds and includes the active zone and where synaptic vesicles cluster.
Synaptic bouton
a synapse formed at thin axons

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