Project Summary/Abstract Healthy vision depends on multiple levels of processing in the retina, the neural tissue that lines the back of the eye. Photoreceptors respond to light and drive signals in retinal interneurons. Interneurons converge onto the retinal ganglion cells (RGCs), the retina's output neurons that project axons through the optic nerve to multiple targets in the brain. All of our visual processing depends on signals generated by the RGCs. The RGCs become injured and die in glaucoma, the leading cause of preventable and irreversible vision loss in humans. A leading risk factor for the development of glaucoma is increased intraocular pressure (IOP). With increased IOP, RGC axons become compromised as they exit the eye to form the optic nerve. Subsequent axon degeneration and RGC death permanently impairs vision. We understand that RGC electrical activity can influence RGC health, and it is known that RGC activity is compromised in mouse models of glaucoma, following either elevations in IOP or direct injury to the optic nerve. Here, we will use two mouse models of optic nerve injury (increased IOP and optic nerve crush) to investigate how these injuries impact RGC activity and identify cellular and synaptic mechanisms underlying the changes in activity. Furthermore, we will consider different categories of RGC types, which have dramatically different responses to glaucomatous injury. Resilient RGCs survive glaucomatous insults well, while susceptible RGCs die quickly after injury. We will test methods for controlling RGC activity in vivo and evaluate the impact of these manipulations on survival for specific RGC types. The experiments will use patch clamp recording in an in vitro preparation of the mouse retina at specific time points following RGC injury and will characterize specific RGC types that are either resilient or susceptible to injuries. Specific Aims will (1) determine underlying cellular and synaptic mechanisms that explain changes in RGC activity following each type of injury; and (2) validate methods for controlling activity in injured RGCs and test their impact on RGC survival. The results will improve our understanding of activity changes in specific RGC types following injury and will facilitate the development of future studies aimed at modulating activity in vivo and improving the survival and regeneration of RGC signaling in human glaucoma.