Type dependent retinal ganglion cell degeneration in glaucoma

Glaucoma is a leading cause of blindness afflicting more than 70 million people worldwide. It is characterized by damage to RGCs that ultimately leads to the death of the cells and vision loss. The diversity of RGC subtypes has been appreciated for decades, and studies, including ours, have shown that RGCs degenerate and die in a type-specific manner in rodent models of glaucoma. The type-specific loss of RGCs results in differential damage to visual and non-visual functions. One type of RGC, the intrinsically photosensitive retinal ganglion cell (ipRGC), expressing the photopigment melanopsin, serves a broad array of non-visual responses to light. Since its discovery, six subtypes of ipRGCs have been described, each contributing to various image forming and non-image forming functions, such as circadian photoentrainment, the pupillary light reflex, the photic control of mood and sleep, and visual contrast sensitivity. The subtype-specific degeneration of ipRGCs and possible associated behavioral changes in animal models and glaucoma patients are reviewed in Chapter 1 of this thesis.
Moreover, to examine the link between subtype-specific ipRGC survival and behavioral deficits in glaucoma, chronic ocular hypertension (OHT) was induced in mice by laser photocoagulation and survival of ipRGC subtypes was characterized. Specifically, I observed that ipRGC subtypes are differentially affected following chronic OHT. While M4 ipRGCs involved in pattern vision, are susceptible to chronic OHT. By contrast, M1 ipRGCs projecting to the suprachiasmatic nuclei (SCN) to regulate circadian rhythmicity, exhibit no cell loss. The cell loss of these subtypes correlates with behavioral observations: though mice with chronic OHT experience reduced contrast sensitivity and visual acuity, circadian re-entrainment and circadian rhythmicity are largely not disrupted in OHT mice. These findings are described in Chapter 2 (published in Journal of Comparative Neurology). These findings provide insight into glaucoma-induced visual behavioral deficits and their underlying mechanisms, which is useful for formulating potential treatments of glaucoma.
Also important for glaucoma management is early intervention as glaucomatous damage is irreversible with the current treatments. Therefore, detecting RGC damages at the earliest stages is essential, though it continues to be a clinical challenge. Taking advantage of visible-light optical coherence tomography fibergraphy (vis-OCTF), we were able to non-invasively track early morphological changes of damaged RGC axon bundles in mice in vivo. Specifically, four parameters: lateral width, axial thickness, cross-sectional area, and the shape of individual bundles were characterized by vis-OCTF. And we found an early axon bundle swelling at 3-days post optic nerve crush, which correlated with about 15% RGC loss, and bundle thinning at 9-days post ONC that correlated with about 60% RGC loss. The morphological transformation of RGC axon bundles monitored by vis-OCTF could serve as a sensitive biomarker for RGC loss, which can be translated to clinical uses in the future. These findings are described in Chapter 3 of this thesis.
Current treatments for glaucoma include drugs and surgeries that alleviate the abnormally elevated IOP, which only slows down, but cannot stop or reverse disease progression, emphasizing the need to better understand glaucoma pathogenesis for future drug development. In Chapter 4 of this thesis, I provide a discussion on the pathogenesis of glaucoma. I propose that RGC loss in glaucoma can be viewed as two separate stages: An initial axonal damage caused by an imbalance of the translaminar pressure gradient (between intraocular pressure and the cerebrospinal fluid pressure). And a secondary soma degeneration caused by impeded trophic support and neuroinflammation. Moreover, I analyze how different RGC types may be differentially affected by various mechanisms contributing to RGC death in glaucoma. For example, the axon collaterals of M1 ipRGCs, may offer protection to these cells in glaucoma as these collaterals do not pass the optic nerve head region and therefore are spared from mechanical and metabolic damage with IOP elevation. Moreover, they may also provide extra target derived trophic support to M1 ipRGCs in glaucoma, etc. With the help of single cell omic technologies, the protective and detrimental molecular pathways underlying type dependent RGC damage can be characterized comprehensively, making the identification of high potential clinical targets possible.