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Robin Kemmler, Thomas Euler, Timm Schubert; Synaptic interactions in the outer retina of the mouse. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1759.
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© ARVO (1962-2015); The Authors (2016-present)
In the outer retina, horizontal cells (HCs) provide inhibitory feedback to cone photoreceptors (cones). This feedback is involved in light adaptation and generation of antagonistic receptive fields. Currently, three feedback mechanisms are described: GABAergic, ephaptic and pH-mediated feedback (reviewed in Thoreson and Mangel, 2012). This study aims at investigating how these feedback mechanisms interact in the mouse retina. In particular, distinct feedback mechanisms could operate in parallel or under different background light conditions.
As all three feedback mechanisms regulate cone output by modulation of voltage-gated calcium channels, our approach was to assess the effect of HC feedback on light-evoked Ca2+ responses measured in cone terminals using 2P microscopy. In the used HR2.1:TN-XL mouse line (Wei et al., 2012), all cone types express the Ca2+ biosensor TN-XL under control of the human red opsin promoter. Feedback mechanisms were pharmacologically dissected using light stimuli of different polarity (i.e. stimuli brighter or darker than background light) and contrast at a mesopic light adaptation state.
Hyper- and depolarizing of HCs via pharmacological manipulations increased and decreased cone resting Ca2+ level, respectively, indicating that inhibitory feedback shifts the Ca2+ channel activation function in cones as described earlier in goldfish retina (Verweij et al., 1996). Blocking GABA receptors did not significantly affect light-evoked cone Ca2+ signals. Manipulation of ephaptic feedback increased both resting Ca2+ level and size of light responses, and decreased the initial peak of dark responses. Preventing fast synaptic pH changes generally did not affect resting Ca2+ level, but surprisingly, similar to ephaptic feedback blockers, also reduced the initial peak of dark responses.
Our data do not support the presence of GABAergic feedback in mouse retina, but suggest the presence of ephaptic and pH-mediated feedback from HCs to cones. Ephaptic feedback seems to be a main regulator for setting the resting Ca2+ level in cones. In contrast, pH-mediated feedback seems to be important for modulating cone output independent of changing the resting Ca2+ level. Taken together, our data suggest that interaction of ephaptic and pH-mediated feedback results in a more complex synaptic signaling in the outer retina.
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