Comparison of Visual Acuity with Decline of Retinal Structure and Function in a Murine Model of P23H Retinitis Pigmentosa – Is There a Role of Plasticity?

Abstract

Purpose : Retinitis Pigmentosa (RP) is an inherited retinal disorder where rod photoreceptors (rods) are lost, followed by cones. A genetic mutation occurs in 25% of autosomal dominant RP (adRP). The most prevalent mutation in North America is a proline to histidine substitution at codon 23 in rhodopsin. We compared changes in visual acuity (VA) with retinal structure/function from early to late-stage disease in a murine P23H Rho ‘knock-in’ mouse model (Rho^P23H/+). To determine a role for plasticity during vision loss, we assessed the same measures in Rho^P23H/+ mice lacking nogo receptor 1 (ngr1), a gene that restricts visual plasticity.

Methods : In the same groups of mice, we evaluated behavioral VA, using the visual water task, and retinal function using the full field electroretinograms (ffERG) at scotopic and photopic levels. We quantified the thickness of the outer nuclear layer (ONL). Assessments were performed at: 1-3, 4-6, 7-9 and 10-12+ months of age (mos). We constructed a natural history for each measure and compared differences between measures over time. We then generated Rho^P23H/+; ngr1^-/- mice and assessed VA, ffERG and retinal morphology in Rho^P23H/+; ngr1^-/-Rho, and in ngr1^-/- mice at similar ages.

Results : Compared to C57Bl6/J (WT), we find a significant decline in Rho^P23H/+ scotopic VA at 1-3 mos (n=9) and in the photopic VA at 7-9 mos (n=16). Rod and cone function and ONL thickness declines as described¹. Rho^P23H/+ scotopic VA decline is significantly slower than ERG decline and VA is retained even when the scotopic b-wave is absent. Between Rho^P23H/+ (n=52, 31, 39) and Rho^P23H/+; ngr1^-/-mice (n=25, 25, 22), the decline of scotopic and photopic VA, as well as retinal structure/function is similar at all ages. In Rho^P23H/+ mice scotopic VA is significantly lower than photopic. Due to a higher scotopic VA, this difference is reduced in Rho^P23H/+;ngr1^-/- mice. Finally, the ngr1^-/- (n=15) photopic b-wave amplitude is significantly larger and the timing of oscillatory potential peaks is faster compared to WT (n=23).

Conclusions : Our natural history show that VA decline is slower than retinal decline in Rho^P23H/+ mice. The absence of ngr1 in Rho^P23H/+ mice does not alter progressive loss of vision. The absence of ngr1 may alters inner retinal function.
¹ Sakami S, et al., 2011 J Biol Chem: 286(12)

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.