The likelihood with which an action potential elicits neurotransmitter release, the release probability (p r ), is an important component of synaptic strength. Regulatory mechanisms controlling several steps of synaptic vesicle (SV) exocytosis may affect p r , yet their relative importance in determining p r and eliciting temporal changes in neurotransmitter release at individual synapses is largely unknown. We have investigated whether the size of the active zone cytomatrix is a major determinant of p r and whether changes in its size lead to corresponding alterations in neurotransmitter release. We have used a fluorescent sensor of SV exocytosis, synaptophysin-pHluorin, to measure p r at individual synapses with high accuracy and employed a fluorescently labeled cytomatrix protein, Bassoon, to quantify the amount of active zone cytomatrix present at these synapses. We find that, for synapses made by a visually identified presynaptic neuron, p r is indeed strongly correlated with the amount of active zone cytomatrix present at the presynaptic specialization. Intriguingly, active zone cytomatrices are frequently subject to synapse-specific changes in size on a time scale of minutes. These spontaneous alterations in active zone size are associated with corresponding changes in neurotransmitter release. Our results suggest that the size of the active zone cytomatrix has a large influence on the reliability of synaptic transmission. Furthermore, they implicate mechanisms leading to rapid structural alterations at active zones in synapse-specific forms of plasticity. release probability | synaptic vesicle docking | active zone cytomatrix | plasticity | pHluorin S ynaptic transmission between most neurons is unreliable as a presynaptic action potential elicits neurotransmitter (NT) release at any individual synapse with a release probability (p r ) of less than one. This probability can vary considerably among synapses of the same axon, often in a target-specific manner (1-3). Similarly, synapses onto a single neuron often display widely varying release probabilities (4-7). Moreover, p r can undergo sustained activity-dependent changes over time (8)(9)(10)(11). These observations suggest that p r is an important determinant of synaptic strength that is tightly controlled by the presynaptic neuron and/or, indirectly, by its postsynaptic target.Although numerous studies have highlighted specific regulatory mechanisms affecting p r of synapses at rest, a concise picture of how p r at individual synapses is determined is only beginning to emerge. Synaptic vesicle (SV) exocytosis is a multistep process during which SVs have to dock at the active zone cytomatrix and undergo a priming step before they are "readily releasable," i.e., immediately available for fusion with the plasma membrane in response to calcium influx through voltage-gated calcium channels (12). Evidence that the size of a synapse's readily releasable pool (RRP) of SVs is closely correlated with its p r (7, 13) suggests that p r is mainly determined by pro...

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