Dynamically primed synaptic vesicle states: Key to understand synaptic short-term plasticity.

Based on evidence that the docked and primed synaptic vesicle state is very dynamic, we propose a three-step process for the buildup of the molecular machinery that mediates synaptic vesicle fusion: (1) loose tethering and docking of vesicles to release sites, forming the nucleus of SNARE-complex assembly, (2) tightening of the complex by association of additional proteins, and partial SNARE-complex zippering, and (3) Ca2+-triggered fusion. We argue that the distinction between "phasic synapses" and "tonic synapses" reflects differences in resting occupancy and stability of the loosely and tightly docked states, and we assign corresponding timescales: with high-frequency synaptic activity and concomitantly increased Ca2+-concentrations, step (1) can proceed within 10-50 ms, step (2) within 1-5 ms, and step (3) within 0.2-1 ms