Early Rod Dysfunction Influences Cone Development in a Rhodopsin P23H Mouse Model of Retinitis Pigmentosa

<b>Background/Objectives</b>: The <i>Rho^P23H/WT</i> mouse line is a commonly used model to study rhodopsin P23H-associated autosomal dominant retinitis pigmentosa. Previous studies in <i>Rho^P23H/WT</i> mice have largely focused on retinal changes occurring at one month of age and later, and have indicated a compensatory thickening of inner retinal layers in response to rod degeneration. However, the effect of disease processes during early postnatal retinal development remains understudied. <b>Methods</b>: In this study, we investigated the retinal response to rod dysfunction during early postnatal developmental ages P8-P24 in our novel <i>Rho^P23H/WT</i> reporter line, <i>Rho</i>P23H.GFP, which expresses green fluorescent protein (GFP) exclusively in cone photoreceptors. <b>Results</b>: Histological analysis revealed no significant difference in retinal thickness in <i>Rho</i>P23H.GFP mice compared to healthy controls at the ages investigated. <i>Rho</i>P23H.GFP retinas initially exhibited a greater mislocalization of rhodopsin to the rod cell bodies at P12, though this mislocalization normalized to wildtype by P24. Most notably, flow cytometry revealed significantly increased cone photoreceptor numbers in P12 (61%), P16 (48%), and P24 (40%) <i>Rho</i>P23H.GFP mice compared to wildtype controls, indicating a possible compensatory response of cone photoreceptors to rod dysfunction. Additionally, cone morphology appeared altered in diseased cones. <b>Conclusions</b>: Our results suggest that cones may undergo a developmental compensatory adaptation in response to rod dysfunction, providing new insights into early disease mechanisms of retinitis pigmentosa.