Compensatory Cone-Mediated Mechanisms in Inherited Retinal Degeneration Mouse Models: A Functional and Gene Expression Analysis

Abstract

The retina undergoes compensatory changes in response to progressive photoreceptor loss/dysfunction; however, studies of inherited retinal diseases (IRDs) often lack a temporal connection between gene expression and visual function. Here, we used three mouse models of IRD - Cnga3^-/-, Pde6c^cpfl1, and Rd1 - to investigate over time the effect of photoreceptor degeneration, particularly cones, on visual function and gene expression. Changes to gene expression include increases in cell survival and cell death genes in Pde6c^cpfl1 before significant cell loss, as well as an increase in cone-specific genes in the Rd1 at the peak of rod death. We show that Cnga3^-/- and Pde6c^cpfl1 mice maintained photopic visual acuity via optomotor responses, despite no recordable cone electroretinogram (ERG), while functional measures and photoreceptors loss were correlated in Rd1 mice. There were also significant changes to oscillatory potentials (OPs) in Cnga3^-/- and Pde6c^cpfl1, implying an effect on inner retinal cells as a result of cone degeneration. These results indicate a potentially malleable retinal environment following cone degeneration; however, further investigation is needed to elucidate how these changes compensate for the loss of cone function.

Keywords: Achromatopsia; Cell death; Inherited retinal disease; Mechanisms; Retinitis pigmentosa; Vision; cnga3; cpfl1; rd1.