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.
Bibliographical noteFunding Information:
This work is supported by Operating Grants from the Canadian Institutes of Health Research (MOP-77610, MOP-81159, MOP-14692, VIH-105441), Natural Sciences and Engineering Research Council of Canada (Discovery Grant, RGPIN-2017-06665) and Canada Research Chair to L.Y.W.; D.A.D. is supported by the Centre National de la Recherche Scientifique, Fondation pour la Recherche Medicale and the Agence Nationale de la Recherche (ANR-2010-BLANC-1411 and ANR-13-BSV4-0016), and his laboratory is a member of the Bio-Psy Laboratory of Excellence. Y.N. was supported by the Japan Society for the Promotion of Science (KAKENHI Grant JP17K07064).