Horizontal cell signaling in the mammalian retina

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The photoreceptor synaptic complex is of great importance as it is a key site for the processing of visual signals, and the transfer of these signals from photoreceptors to downstream neurons in the retina. The focus of this application is on horizontal cells, inhibitory interneurons that send feedback inhibition to photoreceptors, feedforward inhibition to bipolar cells, and autaptic signals to themselves. The prevailing view of horizontal cell function is that these cells mediate lateral inhibition between photoreceptors, contributing to the antagonistic receptive field surrounds found in downstream neurons. However, the cellular mechanisms underlying the contribution of horizontal cells to receptive field properties in mammalian bipolar and ganglion cells has proven quite difficult to determine due in major part to the lack of fundamental information on horizontal cell signaling. The objective of this program is to understand visual processing in the retina with a focus on the synaptic and cellular mechanisms that underlie the initial stages of vision. We will address this objective by determining and testing the synaptic and cellular mechanisms mediating horizontal cell signaling via GABA to photoreceptors and bipolar cells, as well as to themselves. Specific Aim 1: Determine the mechanisms mediating horizontal cell signaling to photoreceptors. Experiments will test how horizontal cells mediate signaling to photoreceptors by A) identifying the complement of tonic GABAAR and GABACR subunits expressed by horizontal cells and B) characterizing the indirect action of GABA on inhibition and disinhibition of photoreceptor Cav channels. Specific Aim 2: Determine the mechanisms mediating horizontal cell feedforward signaling to bipolar cells. Experiments will test how horizontal cells provide tonic GABA-mediated signaling to bipolar cell types by A) identifying the complement of tonic GABAAR and GABACR subunits expressed on the dendrites of ON- and OFF-bipolar cells and B) characterizing the physiological properties of the GABAergic signal provided by optogenetically controlled horizontal cells to bipolar cells. Specific Aim 3: Determine the functional influence of horizontal cell signaling on bipolar cell visual processing. Experiments will test how features of the light responses of representative bipolar cell types are shaped by horizontal cell signaling using HaloTagTM and AMPA-DART, a novel chemogenetic tool to silence horizontal cell output. Proposed studies will further the understanding of fundamental processes mediating early vision. This objective is consistent with the health-related goals of the National Eye Institute for the understanding of retinal circuits and the development of therapeutic approaches and diagnostic tools essential for the treatment and prevention of retinal disease.