Preserving Vision under Stress: RGC Vulnerability to Alkali Burn and Elevated Intraocular Pressure

Abstract

Abstract

Purpose
Retinal ganglion cells (RGCs) serve as the final output neurons of the retina and essential conduits for transmitting visual information to the brain. Given RGCs' inability to regenerate, any RGC loss causes permanent visual deficits, making it critical to understand how pathological insults compromise their survival for developing effective therapeutic strategies. This thesis investigates dysfunction and degeneration of alpha RGC under two clinically important conditions: chemical injury from corneal alkali burns and mechanical stress from elevated intraocular pressure (IOP) relevant to glaucoma.
Methods
We used established mouse models of corneal alkali burn and ocular hypertension. Controlled corneal exposure induced anterior segment damage while allowing assessment of retinal consequences. Pressure-related injury was modeled using acute IOP elevation and sustained ocular hypertension to approximate glaucomatous stress. Direct mechanical pressure was applied to isolate immediate effects on RGC physiology. RGC function was assessed with ex vivo electrophysiology (light-evoked responses, EPSCs, IPSCs). Behavioral visual performance was measured using standard assays, and RGC survival was quantified by immunohistochemistry. To probe mechanism, we used Cx36 knockout mice and pharmacological blockade with meclofenamic acid (MFA).

Results
Results 1: Corneal Alkali Burn Corneal alkali burn produced rapid and measurable disruptions in RGC function that preceded overt cell loss. Within 6 hours, alpha RGCs showed significantly reduced light sensitivity, EPSCs and IPSCs. These functional deficits were followed by a time-dependent increase in RGC loss, peaking at 24 hours, with damage spreading from peripheral to central retinal regions. We identified Cx36-containing gap junctions as key mediators of secondary RGC death in this setting. Both genetic ablation of Cx36 and pharmacological blockade with MFA significantly improved RGC survival after injury.
Results 2: In pressure-related models, the relationship between structural and functional change was nuanced. Acute hydrostatic IOP elevation initially preserved behavioral visual performance despite evidence of delayed RGC loss, suggesting a transient functional reserve among surviving cells. However, this reserve was not durable: sustained ocular hypertension progressively impaired both synaptic transmission and RGC survival, ultimately manifesting in pronounced behavioral impairments. To test whether pressure directly perturbs RGC signaling, we applied controlled mechanical pressure to RGCs. This produced immediate reductions in light sensitivity and synaptic transmission, along with spurious spiking and baseline fluctuations that masked genuine visual signals.
Conclusions
This work elucidates how two major insults—corneal alkali burns and elevated IOP—compromise RGCs through distinct yet converging mechanisms. After alkali burns, early functional decline is followed by rapid, gap junction–mediated secondary death that can be mitigated by Cx36 blockade using genetic or pharmacological approaches. In pressure-related injury, acute elevations can be partially compensated, masking early damage at the behavioral level, but sustained ocular hypertension progressively degrades both synaptic function and cell survival. Direct pressure manipulation experiments provide a mechanistic link between elevated IOP and visual dysfunction by revealing immediate reductions in light sensitivity and synaptic transmission alongside pressure-induced neural noise.
These findings underscore the value of early functional metrics to guide timely, mechanism-based neuroprotection aimed at preserving visual function.

Date of Award	20 May 2026
Original language	English
Awarding Institution	The Hong Kong Polytechnic University
Supervisor	Feng Pan (Chief supervisor) & Chi Wai Do (Co-supervisor)