Fig. 7: Modelling of synchronous and asynchronous release – generation of release probability maps for different active zone geometries.

a Schematics illustrating Ca²⁺ triggering of different release modes. Synchronous release occurs within several milliseconds after an action potential and is triggered by transient local Ca²⁺-nano/microdomains (~10–100 µM range) in the close vicinity of activated VGCCs (2–100 nm range). In contrast, asynchronous release occurs on a time scale of tens to hundreds of milliseconds and is triggered by longer-lasting global changes in presynaptic Ca²⁺ concentration (~1-5 µM range)^{1, 30}. b Schematics of the modelling framework. Action potential-evoked Ca²⁺ dynamics in a presynaptic bouton (left) were simulated using the VCell computational environment on a 10 x 10 x 10 nm mesh (Methods). For each voxel located in the active zone, the obtained Ca²⁺ transients (middle) were used as an input into the allosteric model of Ca²⁺ activation of vesicular fusion⁴² (right) to compute the probability of synchronous release for individual RRP vesicles p_s. As discussed in the text, the probability of asynchronous release p_a was assumed not to depend on the vesicle location in the active zone and its value was constrained based on the experimental data (Methods). c Nine cases of considered active zone geometries (i to ix) and corresponding model-predicted maps of the overall release probability \({p}_{v}={p}_{s}+(1-{p}_{s}){p}_{a}\), and of the relative fractions of synchronous (blue) and asynchronous (red) release modes for the model with endogenous buffering (see also Supplementary Fig. 13 for the model with the intracellular pipette buffer).