Abstract: Optic nerve injury leads to axonal degeneration and the death of retinal ganglion cells, which ultimately causes vision loss. Notably, current treatments are limited. In the present study, we explored whether neurogenic differentiation factor 1 (NeuroD1 or ND1) overexpression in retinal Müller cells may repair the retina after optic nerve crush in mice. Adult mice were subjected to optic nerve crush followed by intravitreal AAV-7m8-GFAP-GFP-ND1 virus injection. Immunofluorescent staining, multi-electrode array recording, electroretinogram, and visual behavior tests were then performed to examine retinal and optic nerve structure and retinal function at various post-optic nerve crush and virus injection times. Western blot analysis and quantitative reverse transcription polymerase chain reaction were performed to explore the possible mechanisms. Compared with the control virus, specific overexpression of ND1 in Müller cells greatly improved the light responses of retinal ganglion cells and retinal neurons in optic nerve crush–injured mice as early as 1–2 weeks post-virus injection and lasted for up to 4 weeks. Neuronal survival in the ganglion cell layer and synaptic connections in the inner retina were slightly improved at 2 weeks; however, visual behavior, retinal ganglion cell survival, and optic nerve structure were not improved. ND1 transiently enhanced glial cell–derived neurotrophic factor expression in the optic nerve crush–injured retina but hardly inhibited retinal inflammation within 2 weeks. Together, our data indicate that ND1 overexpression in Müller cells improves retinal function in the optic nerve crush–injured retina, and suggest that its neuroprotective effect may be caused by enhanced glial cell–derived neurotrophic factor release. 

Key words: glial cell-derived neurotrophic factor, inflammation, Müller cell, NeuroD1, optic nerve injury, retinal ganglion cell, synaptic connection