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Robert G. Smith, Maarten Kamermans; Role Of Synaptic And Potassium Currents For Ephaptic Feedback In The Cone-horizontal Cell Circuit. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4303.
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© ARVO (1962-2015); The Authors (2016-present)
The release of glutamate by the cone ribbon synapse is modulated by horizontal cells through negative feedback, which may comprise several mechanisms. In the ephaptic hypothesis, activation of calcium channels in the cone terminal is shifted by the extracellular voltage gradient, which is controlled by the current flowing into the horizontal cell dendritic tips through AMPA and hemi-Cx channels. It also depends on the resistance of the extracellular space and the input resistance of horizontal cells. Although several important parameters that support this ephaptic mechanism have been measured, exactly how each parameter contributes to the ephaptic negative feedback in a dynamic system is unknown.
We developed a dynamic computational model of ephaptic feedback for an array of cones converging onto a horizontal cell. The model included the membrane potential of cones and the horizontal cell, currents in extracellular space (~1000 MOhm), realistic L-type Ca and Ca-activated chloride channels in the cone terminal, AMPA and hemi-Cx channels in the horizontal cell dendritic tips, and an inwardly rectifying potassium (Kir) channel in the horizontal cell soma. We calibrated the model to produce realistic synaptic release rates (cones: ~100ves/s, dark), and horizontal cell voltages (-35 mV/dark, -80 mV/full-field bright light). We then tested different combinations of the synaptic and membrane conductances for their effect on feedback.
When a central cone in the model was clamped at a typical dark resting potential (-40 mV), and the surrounding cones were clamped at -55mV to simulate a bright flash, the horizontal cell hyperpolarized, increasing the central cone's release rate (~50%), indicating negative feedback. The light response activated the horizontal cell's Kir channels, further hyperpolarizing it, and increasing the current through the AMPA and hemi-Cx channels. This in turn generated a more negative external voltage at the cone membrane, which after a short delay increased the cone's calcium current and vesicle release.
A realistic dynamic model of ephaptic feedback from horizontal cells to cones predicts that the horizontal cell Kir channel is an important exit route for the current entering via the hemi-Cx channels, and that its role is to facilitate negative feedback to the cone.
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