Regulation of presynaptic strength by controlling Ca2+ channel mobility: effects of cholesterol depletion on release at the cone ribbon synapse

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Abstract
Synaptic communication requires proper coupling between voltage-gated Ca2+ (CaV) channels and synaptic vesicles. In photoreceptors, L-type CaV channels are clustered close to synaptic ribbon release sites. Although clustered, CaV channels move continuously within a confined domain slightly larger than the base of the ribbon. We hypothesized that expanding CaV channel confinement domains should increase the number of channel openings needed to trigger vesicle release. Using single-particle tracking techniques, we measured the expansion of CaV channel confinement domains caused by depletion of membrane cholesterol with cholesterol oxidase or methyl-β-cyclodextrin. With paired whole cell recordings from cones and horizontal cells, we then determined the number of CaV channel openings contributing to cone CaV currents ( ICa) and the number of vesicle fusion events contributing to horizontal cell excitatory postsynaptic currents (EPSCs) following cholesterol depletion. Expansion of CaV channel confinement domains reduced the peak efficiency of release, decreasing the number of vesicle fusion events accompanying opening of each CaV channel. Cholesterol depletion also inhibited exocytotic capacitance increases evoked by brief depolarizing steps. Changes in efficiency were not due to changes in ICa amplitude or glutamate receptor properties. Replenishing cholesterol restored CaV channel domain size and release efficiency to control levels. These results indicate that cholesterol is important for organizing the cone active zone. Furthermore, the finding that cholesterol depletion impairs coupling between channel opening and vesicle release by allowing CaV channels to move further from release sites shows that changes in presynaptic CaV channel mobility can be a mechanism for adjusting synaptic strength.

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