Larbi, D.; Chen, S.; Indictor, A.; Gibbons, L. D.; Kang, S.; Rief, A. M.; Wohl, S. G.

We developed a physiologically relevant light damage model in pigmented mice and determine how Muller glial (MG) Dicer1/microRNA (miRNA) loss impacts retinal structure and function after injury. A moderate light damage paradigm (5,000 lux, 4 hours) was developed in pigmented mice carrying the RPE65 Leu450 variant. MG-specific Dicer1 conditional knockout (cKO) mice across three Cre lines (Rlbp1-CreER, Glast-CreER, Ascl1-CreER) were subjected to light damage at different developmental stages. Retinal structure and function were assessed longitudinally using optical coherence tomography (OCT), histology, and electroretinography (ERG). Preconditioning and double-damage paradigms were included as controls. The model induced progressive photoreceptor degeneration with early functional decline preceding structural loss and delayed inner retinal impairment. Across all MG-specific Dicer1-cKO lines, retinas exhibited partial structural preservation and, more prominently, sustained functional preservation following injury. Inner retinal function (Vmax) was consistently maintained despite reduced photoreceptor input. This phenotype was independent of age, timing of MG manipulation, or baseline retinal condition and was not reproduced by preconditioning paradigms. Dicer-deficient MG displayed reduced glial fibrillary acidic protein (GFAP) immunoreactivity, indicating suppression of reactive gliosis; however, reduced GFAP alone was insufficient to confer neuroprotection. MG-specific miRNA depletion induces a neuroprotective retinal state characterized by preserved inner retinal function and reduced secondary degeneration. These results identify MG Dicer/miRNA networks as crucial regulators of injury responses and highlight not only a glia-driven degeneration mechanism but also a potential therapeutic target.