Abstract
Abstract: :
Purpose:An early abnormality in glaucoma appears to be the disturbance of visual motion sensitivity, which has been linked to selective damage to the magnocellular pathway, and a reduction in the proportion of larger retinal ganglion cells with a corresponding loss of larger axons in the optic nerve. This finding however, is controversial. We have investigated the significance of retinal ganglion cell size and the process of apoptosis in different glaucoma–related models of RGC disease. Methods:We assessed rat models of chronic ocular hypertension (OHT, n=20), optic nerve transection (axotomy, n=18), and a newly–developed model of staurosporine–induced RGC apoptosis (n=15). Half the animals in each group underwent superior collicular injections of DiASP 10 days prior to the start of the study. Animals were killed at set time points, and intravitreal fluorescent–labeled annexin 5 was administered immediately before killing. Enucleated eyes were analysed histologically using confocal microscopy. Results:Large RGC apoptosis (defined by a soma size of >7.0 µm radius) accounted for 83.85%, 46.84%, 43.50% and 23.07% of total RGC apoptosis in OHT eyes at 2, 3, 4 & 8 weeks respectively. In axotomised eyes, we recorded large RGC apoptosis in 4.94%, 58.24% and 12.48% at 0.3, 3 & 7 days respectively. Peak large RGC apoptosis occurred at 2 weeks in OHT eyes & 3 days post–axotomy. On analysis of our staurosporine models, we found preferential induction of apoptosis in large RGC soma only at low concentrations (0.125 µg) of staurosporine. Conclusions:We demonstrate early, selective apoptosis of large RGCs in different glaucoma–related models. Recent evidence suggests a relative increase in RGC soma size in the early stages of experimental axotomy and glaucoma, attributed to either a loss of cell volume regulation secondary to neuronal ill health, or attempts by surviving RGC to increase retinal coverage. However, no previous study has investigated the relationship between soma size and RGC apoptosis in glaucoma. Selective magnocellular neuronal apoptosis has previously been demonstrated in hypothalamic lesions, and attributed to large compared to small neurons being more susceptible to the loss of trophic signals. Our model of staurosporine–induced RGC may be a useful tool to study the effects & consequences of selective RGC apoptosis with potential implications for glaucoma.
Keywords: apoptosis/cell death • ganglion cells • pathology: experimental