Mechanisms, functions and utility of RGC oscillation in retinal deafferentation mouse models

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The long-term goal of this application is to elucidate the mechanisms and functions of inner retina oscillation in development and maintenance of the visual system. The proposal is based on the existence of two independent oscillation mechanisms in adult retina. We hypothesize that these oscillation mechanisms are built-in function of the retina, masked by glutamate released by photoreceptor in normal situation but emergent under deafferentation conditions such as photoreceptor degeneration and complete congenital stationary night blindness to ensure stable connection between the eye and the brain. We have found that deleting connexin 36 (Cx36) but not Cx45 genes can silence retinal oscillation. We have also preliminarily tested mice with photoreceptor degeneration but without Cx36 expression and found that retinogeniculate projections become abnormal. Since retinal oscillation appears to have a biological function, it is important to know mechanistic details of the two mechanisms. Aim-1 will thus focus on delineating the cellular origin of the less understood flupirtine-insensitive mechanism. Aim-2 will stringently test the role of oscillation in maintaining retinofugal projections by genetically manipulating Cx36 gene including inducible inactivation in adult animals after photoreceptor degeneration. In order to understand whether retinal oscillation has other functions, it is necessary to know which retinal neurons oscillate and through what mechanisms. Aim-3 will thus survey synaptic inputs onto genetically identifiable RGCs in two retinal deafferentation mouse models and test the hypotheses that mouse RGCs are more diverse than currently appreciated and that group-specific circuit connection characteristics exist to drive RGCs' unique physiological light responses in different groups. A fruitful outcome will in the short-term generate a resource that contains many genetically identifiable RGC types in mouse and in the long-term assign group-specific morphometric features, intrinsic membrane properties, and light response characteristics to them. These efforts fill knowledge gaps, confer a biological function to retinal oscillation in maintaining RGC central projection, and provide a strong foundation for future inquiries into retinal disease mechanisms and treatment window and/or options.