Spatio-temporal characterization of S- and M/L-cone degeneration in the Rd1 mouse model of retinitis pigmentosa

Daniel S Narayan,Glyn Chidlow,Jack Ao,John P M Wood,Robert J Casson

doi:10.1186/s12868-019-0528-2

Abstract

BackgroundThe Pde6brd1 (Rd1) mouse is widely used as a murine model for human retinitis pigmentosa. Understanding the spatio-temporal patterns of cone degeneration is important for evaluating potential treatments. In the present study we performed a systematic characterization of the spatio-temporal patterns of S- and M/L-opsin+ cone outer segment and cell body degeneration in Rd1 mice, described the distribution and proportion of dual cones in Rd1 retinas, and examined the kinetics of microglial activation during the period of cone degeneration.ResultsOuter segments of S- and M/L-cones degenerated far more rapidly than their somas. Loss of both S- and M/L-opsin+ outer segments was fundamentally complete by P21 in the central retina, and 90% complete by P45 in the peripheral retina. In comparison, degeneration of S- and M/L-opsin+ cell bodies proceeded at a slower rate. There was a marked hemispheric asymmetry in the rate of S-opsin+ and M/L-opsin+ cell body degeneration. M/L-opsin+ cones were more resilient to degeneration in the superior retina, whilst S-opsin+ cones were relatively preserved in the inferior retina. In addition, cone outer segment and cell body degeneration occurred far more rapidly in the central than the peripheral retina. At P14, the superior retina comprised a minority of genuine S-cones with a much greater complement of genuine M/L-opsin cones and dual cones, whilst the other three retinal quadrants had broadly similar numbers of genuine S-cones, genuine M/L-cones and dual cones. At P60, approximately 50% of surviving cones in the superior, nasal and temporal quadrants were dual cones. In contrast, the inferior peripheral retina at P60 contained almost exclusively genuine S-cones with a tiny minority of dual cones. Microglial number and activity were stimulated during rod breakdown, remained relatively high during cone outer segment degeneration and loss of cone somas in the central retina, and decreased thereafter in the period coincident with slow degeneration of cone cell bodies in the peripheral retina.ConclusionThe results of the present study provide valuable insights into cone degeneration in the Rd1 mouse, substantiating and extending conclusions drawn from earlier studies.

Highlights

The Pde6brd1 (Rd1) mouse is widely used as a murine model for human retinitis pigmentosa
Cone cell bodies were identified by their wide ovoid morphology and labeled with moderate fluorescent intensity, whilst outer segments were identified by their narrow bundle-like appearance and labeled with high fluorescent intensity (Additional file 2)
Our results showed a homogeneous distribution of M/L-opsin+ cones throughout the Rd1 retina at P14, whilst there was a gradient of S-opsin+ cones, from a relatively sparse population in the superior retina to a high density of cones in the inferior retina (Figs. 1, 2, 3)

Summary

Introduction

The Pde6brd (Rd1) mouse is widely used as a murine model for human retinitis pigmentosa. The Pde6brd (rd/rd, Rd1) mouse is a very widely used model of RP [1, 2], which is increasingly being employed to study the pathogenesis of secondary cone degeneration, and, to explore potential therapeutic interventions to delay this loss of cones. Rod degeneration in this strain occurs due to an autosomal recessive mutation in the beta subunit of rod photoreceptor cGMP-phosphodiesterase [3], the same enzyme defect identified in humans with autosomal recessive RP. The underlying pathogenesis of cone degeneration, both in the Rd1 strain and in RP, remains unclear, a number of mechanisms have been implicated, including depletion of rodderived cone viability factor, oxidative stress, microglial activation, and energetic failure [4,5,6,7]

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