Calcium secretion coupling at calyx of Held governed by nonuniform channel-vesicle topography.

Phasic transmitter release at synapses in the mammalian CNS is regulated by local [Ca2+] transients, which control the fusion of readily releasable vesicles docked at active zones (AZs) in the presynaptic membrane. The time course and amplitude of these [Ca2+] transients critically determine the time course and amplitude of the release and thus the frequency and amplitude tuning of the synaptic connection. As yet, the spatiotemporal nature of the [Ca2+] transients and the number and location of release-controlling Ca2+ channels relative to the vesicles, the "topography" of the release sites, have remained elusive. We used a time-dependent model to simulate Ca2+ influx, three-dimensional buffered Ca2+ diffusion, and the binding of Ca2+ to the release sensor. The parameters of the model were constrained by recent anatomical and biophysical data of the calyx of Held. Comparing the predictions of the model with previously measured release probabilities under a variety of experimental conditions, we inferred which release site topography is likely to operate at the calyx: At each AZ one or a few clusters of Ca2+ channels control the release of the vesicles. The distance of a vesicle to the cluster(s) varies across the multiple release sites of a single calyx (ranging from 30 to 300 nm; average approximately 100 nm). Assuming this topography, vesicles in different locations are exposed to different [Ca2+] transients, with peak amplitudes ranging from 0.5 to 40 microm (half-width approximately 400 microsec) during an action potential. Consequently the vesicles have different release probabilities ranging from <0.01 to 1. We demonstrate how this spatially heterogeneous release probability creates functional advantages for synaptic transmission.