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.

RPE-derived exosomes rescue the photoreceptors during retina degeneration: an intraocular approach to deliver exosomes into the subretinal space

“…The S-cones are sensitive to the short wavelength (blue) light stimulus, while the M cones are sensitive to the medium wavelengths (red) light stimulus. Typically, the well characterized antibodies can bind to the opsin protein in outer segments, thereby distinguishing the two cone populations (Narayan et al, 2019). We show that both the M-and S-cone photoreceptors are rescued by RPE-Exos.…”

Transplanted Pluripotent Stem Cell-Derived Photoreceptor Precursors Elicit Conventional and Unusual Light Responses in Mice With Advanced Retinal Degeneration

“…It is also unlikely that the responses we recorded originate from residual S and M cones reported in previous studies. 45,46 Indeed, after week 12, residual S cones are restricted to the far periphery of the ventral retina, while remaining M cones are located in the far periphery of the dorsal retina 46 ; furthermore, these remaining cones are morphologically abnormal and lack inner and outer segments. 29 Though our responsive RGCs cluster in spatially restricted areas, these areas always stretch from the periphery toward the center, lending support to the fact that they do not reflect surviving cones in the periphery.…”