The Role of Outer Retinal Injury in Glaucoma

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Despite advances in therapy, glaucoma remains one of the leading causes of blindness. In this disease, chronically elevated intraocular pressure (IOP) is a risk factor for optic nerve damage, which has traditionally been thought to occur either by mechanical damage to the retinal ganglion cell (RGC) axons, or by reduced blood flow to the nerve. However, the Principal Investigator and colleagues have recently reported morphologic evidence for injury to the cone photoreceptors in both humans with a diagnosis of glaucoma and in an experimental model of chronic glaucoma. This group has also found evidence for injury at the molecular level. Specifically, that there is decreased production of opsin-specific messenger RNA in the L/M- cones (long and medium wavelength-sensitive) in both experimental glaucoma as well as human glaucoma. Preliminary electrophysiological data also suggest partial functional impairment of the cones, which appears to be most prominent in the arcuate (mid-peripheral) region that is known to be affected earliest in human chronic glaucoma. Based on these findings, an alternative hypothesis is proposed for a mechanism that might contribute to RGC death in glaucoma. Namely, that elevated IOP results in decreased choroidal blood flow causing ischemic injury to the photoreceptors. This is followed by transmission of the damaging effects (perhaps involving elevated levels of glutamate due to decreased re-uptake or transport) in an anterograde direction to the inner retina, leading to or exacerbating RGC injury. The aim of this proposal is to test specific predictions of this anterograde hypothesis relating to alterations in choroidal blood flow and the functional sequence of events that occur in a model of experimental glaucoma. Experiments include: measurement of choroidal blood flow using a microsphere impaction technique, in situ hybridization and mRNAse protection assay with opsin specific probes, and multifocal as well as full-field electroretinography.