Retinal circuit disassembly in primate glaucoma

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PROJECT SUMMARY / ABSTRACT During development, specific synaptic partners connect in order to ensure proper neural circuit function, but how these connections are disassembled during neurodegeneration is less well understood. In rodent experimental glaucoma (EG) models, synapse loss occurs early, preceding retinal ganglion cell (RGC) dendrite retraction and cell death. Converging evidence in rodents suggests that specific RGC types are more susceptible to elevated intraocular pressure, but little is known about retinal circuit disassembly in glaucomatous primate retina. Indeed, significant differences in mice, which lack a lamina cribrosa and macula and have dissimilar RGC types, limit the translation and generalizability of findings to humans. It is critically important to address this knowledge gap in order to advance successful development of clinically relevant diagnostics and novel treatment approaches, such as neuroprotection, gene therapy, and cell-based vision restoration strategies. Here we assemble a highly collaborative team of investigators with complementary expertise well-matched to our goal of systematically determining the connectivity, function, and transcriptomes of RGCs undergoing circuit and synapse disassembly in glaucomatous primate retina. Our approach builds on a well-established rhesus macaque non-human primate (NHP) model of experimental glaucoma that closely recapitulates structural and functional changes observed in human glaucoma, and permits detailed and precise staging of disease. Based on our studies in mice and preliminary data in NHP, we hypothesize that specific microcircuits in the injured adult NHP retina may exhibit susceptibility in connectivity and function, which is reflected in differential gene expression. To test this hypothesis, we apply rigorous quantitative electrophysiological, anatomical, and molecular assessments focusing on the four main RGC types in NHP retina: ON and OFF midget and parasol ganglion cells. Aim 1 will use high-density multielectrode arrays, single cell recordings, and Patch-seq to identify the functional RGC types that are vulnerable in NHP EG and probe their transcriptomes to reveal mechanistic insights and novel therapeutic targets. Aim 2 will determine the specificity and patterns of circuit and synapse disassembly in NHP EG from both lamina-specific and cell type-specific perspectives using detailed circuit and synapse mapping. The proposal is innovative because it brings together multi-modal function, morphologic, and molecular analyses, and is significant because it focuses on the four main RGC types in primate that account for the majority of human vision and are affected in glaucoma. We will generate significant resources for the scientific community and reveal insights into retinal circuit disassembly and the potential for circuit repair in a highly clinically relevant model of glaucoma.