Nr2e3-Deficient Mice Show Evidence for Elevated Photoreceptor Bioenergetics and Retinal Visual Cycle Activity Based on OCT Metabolic Biomarkers.

Purpose: Ex vivo studies show that photoreceptors of Nr2e3-deficient (rd7) mice display (1) cone-like juxtanuclear mitochondria suggesting higher bioenergetics than in wild-type (WT) mice, and (2) reliance on a cone-only "retinal" visual cycle-two hypotheses examined in vivo herein. Methods: We measured two optical coherence tomography (OCT) metabolic biomarkers in normal and rd7 mice, both on a background with inefficient mitochondria (C57BL/6J), under light and dark conditions. The first biomarker is the external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness which contracts in response to subretinal space acidosis limiting retinoid availability. The second biomarker is the sub-ELM hyperreflective band profile shape aspect ratio which increases when the subretinal space is acidotic and mitochondria are inefficient. We also measured retinal layer thicknesses, mitochondrial configuration by electron microscopy (EM), and visual performance using optokinetic tracking. Results: Compared with WT mice, rd7 mice showed more compact mitochondria (EM) distributed over larger-than-normal regions of photoreceptor inner segments (OCT and EM), and subnormal ELM-RPE thickness; OCT biomarkers did not change with light-dark conditions. The outer nuclear layer (ONL) was slightly thinner than normal, and visual performance was normal. Unexpectedly, inner retina thickness was increased. Conclusions: The data suggest that rd7 mice have higher-than-normal photoreceptor metabolism based on widespread distribution of abnormally less elongated mitochondria, and OCT biomarker evidence of more efficient energy production. The slightly thinner ONL despite reduced ELM-RPE thickness/impaired RPE-based retinoid recycling is consistent with rd7 mice using the cone-specific visual cycle to maintain adequate retinoid levels for vision.