Mechanisms of NMDAR contribution to traumatic injury in retinal ganglion cells

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Project Summary Glaucoma is the most prevalent cause of irreversible blindness worldwide. It is estimated that it affects over 3 million Americans and more than 100,000 are blind from this incurable disease. Often, the primary insult in glaucoma is elevated eye pressure, which leads to optic neuropathy and damage to the axons of retinal ganglion cells (RGCs). RGCs are the output neurons of the retina that carry all visual information to other brain regions; their death results in loss of visual function. Current treatment options are focused on addressing elevated intraocular pressure. While this and similar interventions can delay the progression of glaucoma, even with optimal treatment, some visual deficits occur, and vision loss is irreversible. Therefore, there is a critical need for early detection and treatment aimed at neuroprotection. Animal models have proven to be instrumental in understanding the neuropathology of RGC death. Among them, a mouse model of optic nerve crush (ONC) is of particular note because it leads to precisely timed degeneration of RGCs. Mice, like humans, have multiple RGC subtypes that differ in morphology, are embedded in separate neural circuits, and provide distinct visual functions. For reasons that have not yet been identified, many injury types disproportionately affect some RGC subtypes. Understanding the factors that promote cell survival is essential to design strategies to improve disease management. The goal of this proposal is to analyze the role of glutamatergic NMDA receptors to pathological changes in individual RGCs belonging to different subtypes. NMDA receptors are known mediators of calcium overload, excitotoxicity, and their abnormal activation can lead to cell death via multiple pathways. We will take an innovative approach that combines biophysically realistic modeling, electrophysiology, as well as glutamate and calcium imaging to provide a detailed description of the changes in the structure and function of RGCs subjected to traumatic damage. We will focus on the physiological status and responsiveness to stimulation in the injured neuron. This will enable us to elucidate the differences in the metabolic state of the cells and the contribution of parameters associated with the neuronal activity to visual deficits and prognosis. The proposed research will substantially advance our understanding of the mechanisms involved in neuronal responses to damage. The lessons learned in RGC populations will be combined and integrated to develop a comprehensive theoretical description of the impact of neuronal activity on survival after an insult and readily generalized to provide further understanding of other neuropathological conditions. Finally, our research will identify novel targets for potential neuroprotective interventions to preserve visual function.