| Content: | Active zones are specialized presynaptic structures that organize the release of neurotransmitter vesicles at fast transmitting synapses. Active zones display a variety of structures and specializations at different synapses but one generalization is that they are sites where vesicles and voltage gated calcium channels are maintained in close proximity. In many instances calcium (Ca) channels are anchored to vesicle-associated proteins that are part of the docking-release complex. The structure and release properties of amphibian neuromuscular junctions have been extensively studied during the last 50 years and we have built upon this research with our own modeling and experimental data to investigate the effects of active zone micro-geometry for determining release statistics and paired pulse facilitation properties. The tight packing of vesicles and the molecular level co-localization of Ca channels results in high release probability for any vesicle adjacent to an open channel and little cooperativity between the channels in providing the Ca that drives release. Channel colocalization concentrates Ca ions adjacent to vesicles reducing the total Ca influx needed while maintaining high individual vesicle release probabilities. To reduce depression arising from vesicle depletion a only a small fraction of the total available vesicles are released by a single action potential, due in part to low open channel probability that results in a sparse distribution of Ca influx into the active zone. Paired pulse facilitation at these synapses is particularly sensitive to blockade of N-type Ca channels by w-conotoxin which supports the sparse channel opening model and a localized effect of Ca for facilitation restricted to a subsection of an individual active zone within the synapse. These data will be discussed in the context of general principles for the structure and development of central and neuromuscular synapses including the possible role of a local inhibitory surround accompanying the release of a single vesicle which avoids multiple vesicle releases from single channel openings. |
