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

Abstract

Rod-cone degenerations, for example, retinitis pigmentosa are leading causes of blindness worldwide. Despite slow disease progression in humans, vision loss is inevitable; therefore, development of vision restoration strategies is crucial.Among others, promising approaches include optogenetics and prosthetic implants, which aim to bypass lost photoreceptors (PRs). Naturally, the efficacy of these therapeutic strategies will depend on inner retinal structural and functional preservation. The present study shows that in photoinducible I307N rhodopsin mice (Translational Vision Research Model 4 [Tvrm4]), a 12k lux light exposure eliminates PRs in the central retina in 1 week, but interneurons and their synapses are maintained for as long as 9 weeks postinduction. Despite bipolar cell dendritic

Myriocin Effect on Tvrm4 Retina, an Autosomal Dominant Pattern of Retinitis Pigmentosa

“…Light exposure for 1 to 5 min induces a massive photoreceptor death after 24 h; degeneration is mainly limited to the center of the retina while the peripheral area is less affected (effect probably due to the geometry of the eye) (Gargini et al, 2017). The peculiar features of Tvrm4 mutants, including the possibility of inducing retinal degeneration once neuronal development is completed, make them particularly useful for the study of autosomal dominant RP and retinal remodeling (Stefanov et al, 2019).…”

Sectoral activation of glia in an inducible mouse model of autosomal dominant retinitis pigmentosa

“…Other research groups have induced the I307N Rho mouse with short durations of relatively low intensity, but diffuse, lighting in mirrored cages 6,8,10 . In our previous study, we found that longer durations and higher intensities were required to produce retinal degeneration when using overhead light 7 .…”

“…The seemingly opposing capabilities of microglia and Müller glia may appear incongruous during pan-retinal degeneration, but may be reconciled in the context of the lesion boundary in the I307N Rho mouse where pro-survival pathways and clearance of unsalvageable retina must co-exist in close but distinct spaces. Interestingly, Stefanov et al noted that horizontal cell remodeling is most severe at the boundary of retinal degeneration in the I307N Rho mouse, which is suggestive of unique signaling events 10 .…”

“…These characteristics lend to the use of the I307N Rho mouse in preclinical efficacy studies or mechanistic studies. Furthermore, the light-inducible and tunable nature of retinal degeneration in the I307N Rho mouse creates an opportunity for controlled experimentation when compared to other mouse models of RP that experience early retinal degeneration that may overlap with the final stages of retinal development in the postnatal period 7,10 .…”

“…Gargini et al were the first to report activation of microglia and Müller glia at an early time point following illumination of the I307N Rho mouse and suggested that morphologically distinct cells exist in the area of injury when compared to nearby, relatively unaffected retina. They proposed that the model could be an excellent resource for studying cone death, retinal inflammation, and inner retinal remodeling 8,10 . We recently characterized the time-course of light-induced retinal degeneration in this model with spectral-domain optical coherence tomography (SD-OCT).…”