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

Abstract

Background The 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. Results Outer 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. Conclusion The results of the present study provide valuable insights into cone degeneration in the Rd1 mouse, substantiating and extending conclusions drawn from earlier studies.

Investigations Into Bioenergetic Neuroprotection of Cone Photoreceptors: Relevance to Retinitis Pigmentosa

“…The photomicrographs also reveal that, at P60, M/L-opsin + cones are more numerous in the superior retina relative to the inferior retina, whereas S-opsin + cones are far more numerous in the inferior retina. This hemispheric asymmetry in S-opsin + and M/L-opsin + cone expression is in agreement with earlier findings (Lin et al, 2009; Narayan et al, 2019). The very low numbers of M/L-opsin + cones in the inferior retina does not necessarily indicate that dual cones are preferentially lost in the inferior retina, instead it likely reflects the fact that M/L-opsin protein expression is intrinsically very much lower in cones in the inferior retina as compared to the superior retina (Applebury et al, 2000; Haverkamp et al, 2005).…”

Retinal Ganglion Cell Death as a Late Remodeling Effect of Photoreceptor Degeneration

“…All photoreceptor degenerations seem to evolve similarly independently of the initial event [1,13,15,34]. They cause photoreceptor death by apoptosis [10,35], morphological and topographical changes in the surviving photoreceptors [27,36,37,38,39,40,41], deafferentation of bipolar cell populations [28], and retinal glial cell activation [27,35,41,42].…”

“…During the course of photoreceptor degeneration, glial cells are mobilized to the outer retinal layers [22,27,35,41,42,43]; microglial cells become activated and migrate to phagocytose dying photoreceptors [27,35] (Figure 1) and Müller cells become hypertrophic, fill the space left by dead photoreceptors and form a gliotic seal [32,35,41,42,43,44,45,46,47] (Figure 2). Specifically, it has been documented that glial activation is a common theme in photoreceptor degenerations regardless of their aetiology [35,41,48,49], and that treatments that inhibit microglia [27,43,49] or macroglia [50] can influence the course of the disease. This is probably one of the principal hallmarks of the evolution of photoreceptor degenerations [28,51] and will be important for RGC affectation, because if the gliotic seal is not complete, there might be gaps through which RPE cells invade the retina [4,9,10,28].…”

Functional Availability of ON-Bipolar Cells in the Degenerated Retina: Timing and Longevity of an Optogenetic Gene Therapy

“…One of the central questions regarding optogenetic gene therapy in RP is the feasibility of its usage in later the stages of retinal degeneration and remodeling. The C3H rd1 model of RP exhibits several major hallmarks of progressive degeneration ( Figure S1 ), with the first being the death of rods at about 4 weeks of age [ 55 , 56 ]. The rod-less retina retains an outer segments of cones up to 12 weeks of age, with the degenerative process peaking at week 7–8 [ 56 ].…”

“…The C3H rd1 model of RP exhibits several major hallmarks of progressive degeneration ( Figure S1 ), with the first being the death of rods at about 4 weeks of age [ 55 , 56 ]. The rod-less retina retains an outer segments of cones up to 12 weeks of age, with the degenerative process peaking at week 7–8 [ 56 ]. Cone cell bodies, however, are more resistant to RP, and remain functional for prolonged periods of time, evident by the fact that the retinal ganglion cell (RGC) light evoked activity up to 24 weeks of age [ 54 ].…”