Selective inner retinal dysfunction precedes ganglion cell loss in a mouse glaucoma model

Abstract

BACKGROUND/AIMS: To correlate ganglion cell function with defined parameters of the elevated intraocular pressure profile (IOP) in a mouse glaucoma model and to determine the temporal relationship of these functional changes with ganglion cell death. METHODS: Unilateral chronic ocular hypertension was induced in C57BL6/J mice by laser ablation of the limbal episcleral veins. Scotopic flash electroretinograms were recorded after 5, 10, 20, and 40 days to isolate specific outer and inner retinal responses. Inner retinal function was correlated with the pressure differential between treated and non-treated eyes at the time of electroretinographic recording, and with the cumulative IOP insult (the integral of the IOP.time profile). Peripheral and central ganglion cell densities were quantified by Brn-3 immunohistochemistry. RESULTS: Elevated IOP induced a preferential deficit in inner retinal function. The positive scotopic threshold response (pSTR) was suppressed by 68% on day 5, by 50% on day 10, by 54% on day 20 and by 46% on day 40 after laser treatment. Inhibition of the STR correlated with the pressure differential between treated and non-treated eyes but not with the IOP.time integral. Inner retinal dysfunction preceded the progressive death of ganglion cells. Ganglion cell loss occurred preferentially in peripheral retina and correlated with the cumulative IOP insult. CONCLUSION: We have demonstrated specific inner retinal dysfunction in an inducible mouse glaucoma model. STRs are sensitive to elevated IOP per se, and their early suppression reflects ganglion cell dysfunction rather than cell death. The correlation between IOP elevation and suppression of inner retinal function, in the context of the temporal progression of ganglion cell death, suggests that a portion of the IOP-mediated ganglion cell dysfunction may be reversible.