Pattern of retinal morphological and functional decay in a light-inducible, rhodopsin mutant mouse

Abstract

Hallmarks of Retinitis Pigmentosa (RP), a family of genetic diseases, are a typical rod-cone-degeneration with initial night blindness and loss of peripheral vision, followed by decreased daylight sight and progressive visual acuity loss up to legal blindness. Great heterogeneity in nature and function of mutated genes, variety of mutations for each of them, variability in phenotypic appearance and transmission modality contribute to make RP a still incurable disease. Translational research relies on appropriate animal models mimicking the genetic and phenotypic diversity of the human pathology. Here, we provide a systematic, morphological and functional analysis of RhoTvrm4/Rho+ rhodopsin mutant mice, originally described in 2010 and portraying several features of common forms of autosomal dominant RP caused by gain-of-function mutations. These mice undergo photoreceptor degeneration only when exposed briefly to strong, white light and allow controlled timing of induction of rod and cone death, which therefore can be elicited in adult animals, as observed in human RP. The option to control severity and retinal extent of the phenotype by regulating intensity and duration of the inducing light opens possibilities to exploit this model for multiple experimental purposes. Altogether, the unique features of this mutant make it an excellent resource for retinal degeneration research.

Inner retinal preservation in the photoinducible I307N rhodopsin mutant mouse, a model of autosomal dominant retinitis pigmentosa

“…Iba1 is a calcium‐binding protein with a molecular weight of 17 kDa specifically expressed in macrophage/microglia (manufacturer's data sheet). A widely used microglial marker in mouse retina (Gargini et al, ; Guadagni et al, ) produces a staining pattern similar to what observed in our results.…”

“…Photoinduction duration was controlled by a digital clock; during the procedure animals were fully awake and freely moving. Temperature did not change significantly during light exposure (Gargini et al, ). Animals were exposed to 12.000 lx light for 2 min, after which the animals were kept in the chamber in the dark for one additional minute (“cooldown” time) postinduction (PI), then returned to the local animal facility where they were kept in ambient light conditions (below 60 lx) on a 12/12‐hr light/dark cycle, with water and food ad libitum until the time of retinal examination.…”

“…PR death is accompanied by Müller glial activation, also confined to the central, degenerating retina. Similarly, Iba1‐positive microglial cells with a highly activated, amoeboid morphology, invade the outermost layers of central retina, whereas resident microglia retain a normal morphology in peripheral areas (Gargini, Novelli, Piano, Biagioni, & Strettoi, ). The first sign of morphological remodeling of the inner retina is retraction of dendritic arbors from rod bipolar cells (RBCs), decreased metabotropic glutamate receptor 6 (mGluR6) immunoreactivity in the outer plexiform layer (OPL), and displacement of mGluR6 puncta in the inner nuclear layer (INL).…”

“…It is reported that the degenerating central area does not spread over time; but becomes progressively smaller 1 month after the initial photoinduction. Consequently, the amplitude of the scotopic ERG recovers partially, likely because PR cells at the mid‐periphery of the retina can regenerate damaged outer segments (Gargini et al, ).…”

Systemic Treatment with Nicotinamide Riboside is Protective in Three Mouse Models of Retinal Degeneration

“…Subretinal autofluorescent spots observed in vivo by fundus examination in patients and in animal models are considered diagnostic markers for inflammatory responses in retinal damage and disease. 56–60 To test whether NR treatment alters inflammatory responses of the LIRD mice, in vivo fundus examination at the level of the subretinal space was conducted one week following induction of retinal degeneration. Uninduced eyes showed few blue autofluorescent spots at the level of the subretinal space in vivo (Fig.…”