New mouse retinal stroke model reveals direction-selective circuit damage linked to permanent optokinetic response loss.

Abstract

Ischemic insults give rise to severe visual deficits after blood vessel occlusion. In this study we investigated the effects of retinal stroke on the direction-selective circuit of the inner retina in a new adult mouse model. The inner retinal blood flow was interrupted for 60 minutes by ligating the ophthalmic arteries and veins in the optic nerve sheath. The optokinetic response (OKR) was measured to assess ischemia/reperfusion-mediated functional deficits and structural changes were studied by immunohistochemistry. Ischemia/reperfusion induced reactive gliosis and degeneration of the inner retina. The OKR was almost completely abolished from 7 days after reperfusion, whereas approximately 40% of retinal ganglion cells were still alive. Ischemia led to severe degeneration of the processes of starburst amacrine cells (SAC), which cell bodies are in the ganglion cell layer (ON SACs), and to a lesser extent of the dendrites of SACs, which cell bodies are in the inner nuclear layer (OFF SACs). In addition, the elimination of retinal ganglion cells, direction-selective ganglion cells, and ON SACs was much greater at 10 days and 21 days than that of OFF SACs. After reperfusion, P-Stat3 was transiently activated in ganglion cells, whereas P-Erk1/2 signal was specifically detected in Müller glia. These results show a pronounced destruction of the ON direction-selective circuit in the inner retina that correlated with the irreversible loss of the OKR early after ischemia/reperfusion.