How can exocytosis account for the actual properties of miniature synaptic signals?

It is broadly accepted that a postsynaptic "miniature" is the most elementary chemically transmitted signal and results from the all-or-none release of transmitter packaged in a single presynaptic vesicle. Hitherto, it has not been possible to directly verify this renowned representation, although it is consistent with evidence of vesicle traffic and, following an intense period of release, vesicle depletion. However, vesicle traffic involving molecular components similar to those implicated in transmitter release has been attributed to other functions including membrane repair. Furthermore, as a number of investigators have recently proposed, miniature signals recorded at peripheral and central synapses may actually reflect several rather than a single discharge of transmitter. It is not clear whether such putative multiple-discharge miniatures represent near-synchronous exocytoses of several vesicles or a burst of openings in a pore that couples a vesicle with the outer membrane. In any case, despite the popularity of the vesicular hypothesis, the molecular mechanism involved in synchronizing fast elementary secretion has not yet been elucidated. Interdependencies among subminiature discharges composing a miniature have suggested that the underlying process is a regenerative signal restricted to a presynaptic terminal unit, confirming Fatt and Katz's first speculation on miniatures, which was not vesicular exocytosis [Fatt and Katz (1952), J. Physiol., 117:109-128]. Here we discuss the possibility that this regenerative signal might be a localized cytosolic Ca2+ transient and attempt to reconcile this hypothesis with the exocytotic models proposed to explain fast transmitter release.