title: An Exclusion Zone for Ca2+ Channels around Docked Vesicles Explains Release Control by Multiple Channels at a CNS Synapse.
abstract: The spatial arrangement of Ca2+ channels and vesicles remains unknown for most CNS synapses, despite of the crucial importance of this geometrical parameter for the Ca2+ control of transmitter release. At a large model synapse, the calyx of Held, transmitter release is controlled by several Ca2+ channels in a "domain overlap" mode, at least in young animals. To study the geometrical constraints of Ca2+ channel placement in domain overlap control of release, we used stochastic MCell modelling, at active zones for which the position of docked vesicles was derived from electron microscopy (EM). We found that random placement of Ca2+ channels was unable to produce high slope values between release and presynaptic Ca2+ entry, a hallmark of domain overlap, and yielded excessively large release probabilities. The simple assumption that Ca2+ channels can be located anywhere at active zones, except below a critical distance of ~ 30 nm away from docked vesicles ("exclusion zone"), rescued high slope values and low release probabilities. Alternatively, high slope values can also be obtained by placing all Ca2+ channels into a single supercluster, which however results in significantly higher heterogeneity of release probabilities. We also show experimentally that high slope values, and the sensitivity to the slow Ca2+ chelator EGTA-AM, are maintained with developmental maturation of the calyx synapse. Taken together, domain overlap control of release represents a highly organized active zone architecture in which Ca2+ channels must obey a certain distance to docked vesicles. Furthermore, domain overlap can be employed by near-mature, fast-releasing synapses.
authors.affiliation: Blue Brain Project, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Keller
authors.affiliation: Laboratory of Synaptic Mechanisms, Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Norbert
authors.initials: N
authors.lastname: Babai
authors.affiliation: Laboratory of Synaptic Mechanisms, Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Olexiy
authors.initials: O
authors.lastname: Kochubey
authors.affiliation: Laboratory of Synaptic Mechanisms, Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Han
authors.affiliation: Blue Brain Project, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Henry
authors.initials: H
authors.lastname: Markram
authors.affiliation: Blue Brain Project, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Felix
authors.initials: F
authors.lastname: Schürmann
authors.affiliation: Laboratory of Synaptic Mechanisms, Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schneggenburger
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D065096:Calcium Chelating Agents; D019295:Computational Biology; D003198:Computer Simulation; D004533:Egtazic Acid / Q000031:analogs & derivatives; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D013269:Stochastic Processes; D013569:Synapses / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism; D065833:Trapezoid Body / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D065096:Calcium Chelating Agents; D004533:Egtazic Acid; C046770:EGTA acetoxymethyl ester