Synaptic heterogeneity is widely observed but its underpinnings remain elusive. We addressed this issue using mature calyx of Held synapses whose numbers of bouton-like swellings on stalks of the nerve terminals inversely correlate with release probability (Pr). We examined presynaptic Ca 2+ currents and transients, topology of fluorescently tagged knock-in Ca 2+ channels, and Ca 2+ channel-synaptic vesicle (SV) coupling distance using Ca 2+ chelator and inhibitor of septin cytomatrix in morphologically diverse synapses. We found that larger clusters of Ca 2+ channels with tighter coupling distance to SVs elevate Pr in stalks, while smaller clusters with looser coupling distance lower Pr in swellings. Septin is a molecular determinant of the differences in coupling distance. Supported by numerical simulations, we propose that varying the ensemble of two morphological modules containing distinct Ca 2+ channel-SV topographies diversifies Pr in the terminal, thereby establishing a morpho-functional continuum that expands the coding capacity within a single synapse population.
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© 2019, The Author(s).