Clinically Relevant Outcome Measures for the I307N Rhodopsin Mouse: A Model of Inducible Autosomal Dominant Retinitis Pigmentosa

Abstract

PurposeThe I307N rhodopsin (Rho) mouse is a light-inducible model of autosomal dominant retinitis pigmentosa (adRP) that may be useful in testing therapies. We investigated the time-course of retinal changes of the I307N Rho mouse with spectral-domain optical coherence tomography (SD-OCT).MethodsSD-OCT was performed up to day 30 after light damage; electroretinography (ERG) was employed to evaluate photoreceptor function. We utilized ImageJ to analyze reflectivity of the retina. We used light and electron microscopy to assess retinal organization. We stained synaptophysin and zonula occludins-1 with immunohistochemistry to determine injury to the plexiform layers and retinal pigment epithelium (RPE). We performed lectin staining to evaluate retinal blood vessels.ResultsRetinal degeneration increased with longer exposures to light. An increase in retinal thickness was detected by SD-OCT on day 1 after light challenge followed by loss of the outer nuclear layer (ONL) by day 8. Degeneration was most severe in the nasal and inferior retina. Hyper-reflectivity on SD-OCT developed as early as 1 day after light exposure. Disorganization of the ONL, condensation of photoreceptor chromatin, disruption of the outer limiting membrane, and disarray of outer segments were associated with the hyper-reflectivity. Retraction of the outer plexiform synapses and resorption of the subretinal detachment contributed to retinal thinning. The RPE remained intact, whereas atrophied major retinal vessels were evident after light damage.ConclusionsOur time-course analysis of retinal degeneration in the I307N Rho mouse with SD-OCT and other outcome measures should enable the use of the mouse model in preclinical efficacy studies and mechanistic studies.

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

“…We previously reported that a hyper-reflective signal develops in the ONL of the I307N Rho mouse during retinal degeneration on day one 7 . Therefore, we sought to determine if the area within which the microglia manifest an activated morphology coincides with the area of hyper-reflectivity on SD-OCT at the four hour time point when we both expected a mature hyper-reflective signal and distinct microglia morphology.…”

“…The I307N Rho mouse model of light-induced adRP recapitulates some crucial aspects of patients with the B1 phenotype, including sectoral and variably penetrant retinal degeneration [6][7][8][9] . These characteristics lend to the use of the I307N Rho mouse in preclinical efficacy studies or mechanistic studies.…”

“…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 .…”

“…The generation and characterization of the I307N Rho mouse model was conducted over a decade ago by Budzynski et al and has gained popularity among research groups in recent years [6][7][8]10,11 . 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.…”

“…We demonstrated that a hyper-reflective signal and retinal swelling were evident in the acute period following light challenge, which was followed by near-complete loss of the outer nuclear layer (ONL) within a week. We argued that these SD-OCT findings could be utilized as endpoints to produce an optimized preclinical efficacy study 7 . Recently, Zhang et al demonstrated that whole-body exercise in the I307N Rho mouse mitigated both retinal inflammation, characterized by reduced microglia adherence to the RPE, and visual decline 11 .…”