Understanding synaptic complexity: Parallel feedback mechanisms in the mouse retina

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The first synapse of the visual system plays a fundamental role for all subsequent processing steps: It must provide a reliable, high-fidelity signal flow from the cone photoreceptors to second order neurons of the retina under a wide range of illumination conditions. Here, cone photoreceptors form complex synapses with dendrites of both horizontal cells and bipolar cells. Different types of bipolar cells relay the cone output to signal pathways with different functional properties. Horizontal cells form a single electrically-coupled lateral interneuron network and modulate cone output via feedback synapses, and thus, adjust the cone output gain as a function of background illumination as sensed by the network. The connections from horizontal cells to cones have been intensively studied for several decades but to date we still lack a comprehensive and coherent picture of the mechanisms underlying the modulation of cone output by HCs and their role in retinal light adaptation. Three different synaptic mechanisms have been described to mediate feedback: GABA-mediated feedback, hemichannel-mediated ephaptic feedback, and proton- (pH-) mediated feedback. Contradictory findings with respect to multiple feedback mechanisms within a single species may result from different adaptation states and/or the different experimental conditions. Thus, it is still unclear if the different feedback mechanisms act in parallel or if they part of a multifaceted feedback network as proposed recent studies. Furthermore, it is not clear whether/how the pathways might be functionally connected. By combining three genetic approaches - (i) a transgenic mouse line, in which cones selectively express a genetically encoded calcium biosensor, (ii) horizontal cells transfected with viruses encoding calcium and chloride biosensors, and (iii) gene-silencing techniques to knockdown hemichannels in horizontal cells - with two-photon calcium imaging we want to unravel the synaptic mechanisms that underlie light adaptation in the mouse outer retina. In particular, we aim at probing the HC feedback mechanisms present at different background light levels first directly in the cone axon terminals (as an effect on cone output), and then in HC dendrites (as the presynaptic signal that generates feedback). To gain insight into the spatio-temporal aspects of different feedback mechanisms, we will analyze how chromatic input from spectrally different (green and blue) cone types is integrated in HCs both at the anatomical and the functional level, and then study how this input is translated into (local and/or global network) feedback. We think that a comprehensive outer retina feedback model system may provide new impulses for studies of parallel synaptic mechanisms in other neuronal circuits of the brain.