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M Kamermans, I Fahrenfort, T Sjoerdsma; GABAergic Modulation of Ephaptic Feedback in the Outer Retina . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2920.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: In Goldfish, both cones and horizontal cells (HCs) have ionotropic GABA-receptors (Kaneko, 1986; Verweij, 1998) and HCs release GABA using a GABA transporter (Yazulla, 1982; Schwartz, 1987). It has been proposed that HCs feed back to cones via this GABAergic system. However, full-field light stimulation does not lead to a closure of a GABA-gated conductance in the cones. Instead, negative feedback from HCs to cones is mediated via an ephaptic mechanism involving hemichannels (Kamermans, 2001). This leaves the role of the GABAergic system, present in the outer retina, unexplained. Methods: Single cell electrophysiology on isolated goldfish retinas. Results: Here we show that the GABAergic system modulates the amplitude of the feedback-mediated responses in both cones and HCs. This modulation depends on the GABA-receptors in the cones. Changing the outward GABA-gated current of the cones into an inward current, by manipulating the chloride equilibrium potential in cones, abolishes the modulatory effect of GABA. We propose the following mechanism. Current flows into the hemichannels on the horizontal cell dendrites. This current induces a voltage drop along the intersynaptic space in the synaptic terminal, making the extracellular potential near the Ca-channels slightly negative. This forms the basis for the ephaptic negative feedback mechanism. Since part of the GABA-gated channels of the cone are in the cone/HC synapse, the GABA-gated current flowing out of the cone can provide part of the hemichannel current, and thereby decrease the amount of current flowing through the intersynaptic space from outside the synaptic terminal. This GABAergic redirection of the hemichannel-mediated current leads to a decrease in voltage drop in the intersynaptic space leading to a decrease of feedback. Estimates of the time-constant of the modulatory effect of GABA indicate that it is larger than 5 sec. Immunolocalization of GAT1, GAT2 and GAT3 revealed that the majority of the transporters on HC are outside the cone/HC synapse (Klooster et al., ARVO 2002). This suggests that HCs release GABA in a large extrasynaptic compartment. Conclusion: This organization might account for the slow time constant of the GABAergic modulation. Since the GABA-release is high in the dark-adapted retina, this mechanism down regulates feedback in that condition.
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