Synaptic vesicle undocking induces low-frequency depression

Synaptic depression is often attributed to a depletion of the readily releasable pool (RRP) following exocytosis. However, in certain mammalian central synapses, repetitive presynaptic stimulation at a low frequency of 5 Hz can lead to synaptic depression known as low-frequency depression (LFD). To understand the underlying mechanisms, researchers analyzed the number of synaptic vesicles released at individual active zones during LFD.

Contrary to depletion models, the study found that LFD is not dependent on previous SV consumption. Instead, LFD exhibits a long recovery time course of tens of seconds when challenged with isolated stimulations, but is immediately reversed by a high-frequency train. The researchers propose that LFD results from undocking, a shift between two classes of synaptic vesicles organized sequentially within the RRP.

One class represents replacement vesicles, while the other class is docked. Undocking favors the upstream (replacement) state.

The recovery of LFD depends on stimulation frequency, which the researchers explain as follows: while undocking becomes apparent hundreds of milliseconds after a stimulation, calcium-dependent docking occurs within just a couple of milliseconds. Double presynaptic stimulations alleviate LFD by favoring vesicular docking and replenishing the RRP, in line with the undocking model.

Finally, the study expands the undocking model to explain how stimulation frequency shapes short-term synaptic depression. The researchers found that depression occurs at low frequency, while a facilitation-depression sequence emerges at medium- or high-frequency trains.