UCSF

Glaucoma is a major cause of blindness worldwide, and is characterized by the progressive loss of retinal ganglion cells (RGCs). Although elevated intraocular pressure (IOP) has been identified as a principal risk factor, IOP-reducing treatment does not always lead to favorable clinical outcomes. Delineating the cellular and molecular mechanisms of glaucoma pathogenesis is therefore instrumental in designing IOP-independent neuroprotective interventions. This dissertation uses an experimental model of mouse glaucoma to explore the mechanisms of axonal degeneration, with a focus on the optic nerve head (ONH) generally accepted as an important site of initial axon injury.

I first established and characterized Laser-Induced Ocular Hypertension (LIOH) in albino mice as an experimental glaucoma model. IOP elevation is triggered by photocoagulation of the aqueous humor outflow pathway, resulting in pathologies that recapitulate characteristics of glaucoma. This study offers the research community a temporally-controlled new tool amenable to both pharmacological and genetic manipulations.

I next investigated the role of EphB/ephrin-B signaling in this experimental model. EphB and ephrin-B mRNAs are upregulated in ONH axons and glia early in glaucoma, and reverse ephrin-B signaling is preferentially activated in morphologically normal compared to aberrant axons. Genetic ablation of EphB2 or EphB3 results in more severe axonal degeneration, while C-terminal truncation partially reduces the effect of EphB2, suggesting that the EphB/ephrin-B system protects axons against glaucomatous injury via bidirectional signaling.

In the third project, I present evidence of localized excitotoxicity that plays a role in RGC axonal degeneration. Ectopic accumulation of synaptic vesicle-like structures can undergo exocytosis and release glutamate at the glaucomatous ONH. Pharmacological antagonism of glutamate signaling preserves RGC axon integrity in vitro and in vivo. Cre/loxP-mediated deletion of the vesicular glutamate transporter VGLUT2 or the obligatory NMDA receptor subunit NR1 in RGCs confers protection against axonal degeneration, supporting the in vivo significance of this pathway.

Together, these findings provide insight into the complex pathways activated by IOP elevation in glaucoma, involving both pro-survival and pro-degeneration signals. Improved understanding of these mechanisms may contribute to combinatorial therapeutic strategies that tip the balance toward intrinsic neuroprotective programs while mitigating the effect of pathogenic pathways.