Phenotypic differences between two mouse models carrying defects in the retinoid cycle genes Rdh5 and Rpe65

Abstract

Abstract: : Purpose: The retinoid cycle is the enzymatic pathway by which all–trans–retinal from photoreceptor bleaching is isomerized to 11–cis–retinal in the retinal pigment epithelium (RPE) for visual pigment regeneration. The aim of this work was to compare the phenotype of two animal models with a disturbance of this cycle, the 11–cis–retinol dehydrogenase (RDH5) knock–out mouse and the RPE65 knock–out mouse. Methods:Fully dark–adapted mice were studied by scotopic and photopic electroretinography (ERG) using previously reported protocols. Fundus images were obtained with a confocal SLO (Heidelberg Retina Angiograph, Heidelberg Engineering). The integrity of the vascular system was investigated by means of fluoresceine and indocyanine green (ICG) angiography. Ultrastructural changes were assessed by light and electron microscopy. Results: Whereas the ERGs of RDH5^–/– mice were comparable to those of controls, those of RPE65–deficient mice were seriously affected as previously described. In contrast to the functional differences, both models displayed similar white, autofluorescent dots in the retinal pigment epithelium layer. These dots most likely correlate with the large retinyl ester inclusions found microscopically, and may be the basis for those found in RDH5–deficient Fundus Albipunctatus and some of RPE65–deficient Leber’s Congenital Amaurosis (LCA) patients. No abnormalities in the retinal and choroidal vasculature of the animals were observed. Conclusions: For the first time, fundus changes –similar to those associated with RPE65 deficiency– were observed in RDH5 knockout mice, which make it improbable that the retinyl ester storage itself is a cause of the functional impairment in LCA. The discrepancy between the similar fundus appearance and the difference in retinal function may be attributed to the subtotal disruption of the retinoid cycle in RDH5^–/– mice in comparison to the practically total one in RPE65^–/– mice.

Keywords: electroretinography: non–clinical • imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound) • retinal pigment epithelium