The scheme, above, depicts our working model of rate-limiting steps in the synaptic vesicle cycle in presynaptic terminals. The rate-limiting steps cause short-term depression in the strength of the signal sent to postsynaptic neurons when synapses are used repetitively, as they often are in nature. The strength of the signal is termed the connection strength. Mechanisms that temporarily enhance the connection strength - termed short-term enhancement - are typically activated by the Calcium ions that enter the presynaptic terminal during the same patterns of repetitive use that generate depression, and can complicate attempts to measure the rate-limiting mechanisms. However, the enhancement mechanisms do not cancel depression, but instead work by increasing the efficiency of the machinery that catalyzes exocytosis (i.e., represented by the β parameter in the upper right panel) and, because of this, play a fascinating role in information processing that is orthogonal to the depression mechanisms.
Key differences between our working model and those of other research groups are: (1) before undergoing exocytosis, vesicles laden with neurotransmitter dock to the inside of the plasma membrane at a variety of specialized release sites that differ in how efficient they are at catalyzing exocytosis (magenta versus green donuts in upper left panel); and (2) each docked vesicle is attached to an autonomous pool of reserve vesicles via links between vesicles (yellow).
We first proposed the concept of autonomous reserve pools in Gabriel et al. (2011) to explain simplifying mathematical constraints that emerged from electrophysiological studies of Schaffer collateral synapses. Since then, we have published a morphological analysis confirming that the links between vesicles are present in the correct numbers and can bear enough force to hold the vesicles close together (Wesseling et al., 2019).
The variation among release sites in the efficiency at catalyzing exocytosis emerged from studies of a variety of synapse types, but the basic ideas and evidence are articulated best in Mahfooz et al (2015) and Raja et al (2019). Click here for why we believe that slow-releasing or reluctantly releasable readily releasable vesicles are immediately available for release and undergo exocytosis directly with no requirement to transition to a fast-releasing or super primed state, at least during ongoing stimulation (see the "Alternate scenario" subsection of the figure legend), and here for evidence that the number of reluctantly releasable vesicles correlates with the paired-pulse ratio of synaptic responses at the beginning of a train of stimulation, suggesting strongly that this continues to be true when synapses are resting.
Finally, the functional independence of release sites in our model suggests that synapses function as arrays of individually tunable band pass frequency filters, which, if true, could have important implications for how we think about information processing in biological systems in general.