Inner retinal preservation in the photoinducible I307N rhodopsin mutant mouse, a model of autosomal dominant retinitis pigmentosa. Issue 9 (18th December 2019)

• Record Type: Journal Article
• Authors: Stefanov, Antonia; Novelli, Elena; Strettoi, Enrica
• Is Part Of: Journal of comparative neurology. Volume 528:Issue 9(2020)
• Page Start: 1502
• Page End: 1522
• Publication Date: 2019-12-18
• Subjects: bipolar cell -- dendrites -- retinitis pigmentosa -- rhodopsin -- synapse; Comparative neurobiology -- Periodicals; Neurology -- Periodicals; 616
• DOI: 10.1002/cne.24838
• Languages: English
• ISSNs: 0021-9967

Abstract

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 retraction and moderate loss of horizontal cells, the survival rate of various cell types is very high. Significant preservation of conventional synapses and gap junctions in the inner plexiform layer is also observed. We found the number of synaptic ribbons to gradually decline and their ultrastructure to become transiently abnormal, although based on our findings intrinsic retinal architecture is maintained despite complete loss of PRs. Unlike common rodent models of PR degeneration, where the disease phenotype often interferes with retinal development, in Tvrm4 mice, the degenerative process can be induced after retinal development is complete. This time course more closely mimics the timing of disease onset in affected patients. Stability of the inner retina found in these mutants 2 months after PR degeneration suggests moderate, stereotyped remodeling in the early stages of the human disease and represents a promising finding for prompt approaches of vision restoration. Abstract : Tvrm4 rhodopsin mutant mice undergo rapid photoreceptor loss upon bright light exposure. Early consequences on the inner retina involve mainly second‐order neurons and include quick dendritic retraction and axonal shrinkage in rod bipolar cells (RBCs) and, later, in cone BCs and the presence of anomalous globular synaptic ribbons (GR). Yet, BC survival is nearly 100% and retinal architecture is overall well preserved. Hence, early remodeling in this adult mutant is moderate and similar to what observed in developmental paradigms of retinitis pigmentosa.