Acute IOP Elevation in Mice Alters Light Response Sensitivity of Ganglion Cells and AII Amacrine Cells

Abstract

Purpose: : Glaucoma is a leading cause of blindness, and elevated intraocular pressure (IOP) is the most significant single risk factor for both development and progression of glaucoma. IOP is also currently the only modifiable risk factor identified. While retinal ganglion cell (RGC) death has long been identified as a component of glaucoma, the mechanisms of RGC death and the preceding RGC dysfunction are largely unknown. ON- and OFF-RGCs receive cone inputs from cone depolarizing and hyperpolarizing bipolar cells (DBC_Cs and HBC_Cs), respectively, via chemical synapses. They receive rod inputs from rod DBCs through AII amacrine cells (AIIACs), which make electrical synapses on DBC_Cs and chemical synapses on HBC_Cs and OFF-RGCs. In this report, we describe changes in ON-RGC, OFF-RGC and AIIAC light responses obtained from a mouse model of acutely elevated IOP induced by episcleral venous ablation.

Methods: : C57Black6J mice were used for all experiments. IOP was elevated in one eye via argon laser ablation of three episcleral veins (generally sparing the superior vessel). Experiments were performed at 1 and 2 weeks after ablation. Mice were dark-adapted for at least 1-2 hours prior to all experiments. Light-evoked current responses were recorded from ganglion cells and AII amacrine cells under voltage clamp conditions in living retinal slices, and the cell morphology was determined by Lucifer yellow fluorescence.

Results: : Both ON- and OFF-RGCs show a sensitivity decrease to 500 nm light 2 weeks after laser ablation. A similar sensitivity decrease was observed in AIIACs 1-2 weeks after laser treatment. Response-intensity relations of the AIIAC responses indicate that the first phase of high-IOP-induced AIIAC change is likely to be mediated by disruption of the DBC_R→AIIAC glutamatergic synapse.

Conclusions: : One of the first signs of glaucoma is a general decrease of visual sensitivity. In a mouse model for acute elevation of IOP, both ON- and OFF-RGCs are found to exhibit sensitivity loss before RGC degeneration. This early sensitivity loss is likely to be mediated by defective DBC_R→AIIAC synapses, and identifying ways to prevent damage to these synapses may be a useful strategy for treatment/prevention of glaucoma.

Keywords: ganglion cells • amacrine cells • intraocular pressure