Retinal ganglion cell death in acute and chronic models of glaucoma: Is the degeneration subtype specific?

Glaucoma, the world's leading cause of irreversible blindness, is a group of optic neuropathies with multifactorial etiologies that lead to optic nerve degeneration and retinal ganglion cell (RGC) death, severing the communication between the eye and the brain causing vision loss. As glaucoma is a progressive disease, many ocular changes occur before the actual vision loss and needs comprehensive eye examination to detect these changes. One of the major risk factors of glaucoma is elevated intraocular pressure (IOP), a modifiable factor which is targeted by current therapeutic strategies. None of the available therapies cure the disease but are used to manage it by slowing its progression. Because glaucoma is such a complex disease with many different cellular and molecular pathways at play, a therapy to cure or reverse the disease is not yet developed. RGC neurons are the ones affected in glaucoma. There are about 50000 RGCs per retina. Nerve fibers from these neurons combine together in an optic nerve and relay visual cues transported from other neurons of the retina to the brain. There are more than 30 different subtypes of RGCs that differ in morphology, dendritic arborization, physiological properties and molecular signatures. These RGCs detect different visual signals and project to their respective visual centers in the brain. As these RGCs differ in so many aspects, a lot of studies postulate that they their response to glaucomatous injury also differs in a way that some RGCs are more susceptible to injury than the others. We hypothesize that RGC subtypes are differentially susceptible to glaucomatous injury. To test this hypothesis, we used transgenic animals expressing GFP in individual RGC subtypes and subjected them to glaucomatous insults by using optic nerve crush model (induced model of glaucoma) or nee model (experimental glaucoma model of early onset glaucoma). Our data suggests that RGCs do have a specific pattern of degeneration in under glaucomatous insults. In our induced and inherent models, we found that melanopsin positive RGCs are the most resilient to injury. We also found that axonal degeneration in RGC subtypes after glaucomatous insult is independent of their respective somal degradation. In this study we have also discussed degeneration and regeneration in the central nervous system (CNS) as well as utilized imaging techniques to evaluate individual RGC subtype projections in the brain through its retinorecipient areas.