Disabling Muller Glia Preserves Retinal Function After Retinal Injury

Abstract

We developed a physiologically relevant light damage model in pigmented mice and determined how Muller glial (MG) Dicer1 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 using optical coherence tomography (OCT), histology, and electroretinography (ERG). Preconditioning and double-damage paradigms were included as controls. The model induced progressive photoreceptor degeneration characterized by early functional decline, followed by structural loss and delayed inner retinal impairment. Across all lines with Dicer loss in MG, retinal structure and function were better preserved following injury than in light-damaged controls. The most sustained protective phenotype was observed in the Rlbp1-CreER-driven line. 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 a potential suppression of glial reactivity. However, the absence of a neuroprotective phenotype following preconditioning suggests that reduced GFAP expression alone is insufficient to account for the observed retinal preservation. Collectively, these findings demonstrate that MG-specific Dicer1 deletion is associated with a neuroprotective retinal phenotype characterized by preserved inner retinal function and reduced secondary degeneration. These findings establish a glia-driven component of retinal degeneration and demonstrate that altering the MG injury response can preserve retinal function following injury.