Abstract
Purpose :
Retinitis pigmentosa (RP), a hereditary degeneration of rod and cone photoreceptors causing blindness, affects approximately two million people worldwide. Here, we study RP in a Pde6brd10 mutant mouse model (rd10) and analysed, which upstream alterations affect light-evoked retinal ganglion cell (RGC) response properties in comparison to wild-type (WT) retina at different stages of degeneration.
Methods :
We investigated functional RGC diversity during the progression of photoreceptor degeneration. To this end, we recorded light-evoked responses of RGCs using 2-photon calcium imaging in rd10 (n=9 mice, both sexes) and WT (C57BL6/J, n=14) retinae at defined postnatal (P) time points P30, P45, P90, and P180 and different retinal locations. To analyse functional diversity, we determined “functional fingerprints” of RGCs to measure spatio-temporal response features as a function of degeneration stage. Student’s t-test, Pearson correlation and Jensen-Shannon-Divergence were used for statistical analysis.
Results :
We observed that responsiveness of rd10 vs. WT RGCs dropped significantly first around P45 (p=3.57e-05), reached a plateau at P90 (p=0.246) and then further dropped at P180 (p=2.4e-08). Interestingly, we found that all five functional sets of RGCs (OFF, ON-OFF, fast ON, slow ON, and "uncertain RGCs") are still present in rd10 retinae at least until P90. In particular, some RGC response features, such as orientation- and direction-selectivity, hardly change qualitatively. At P45, the number of ON-OFF (p=0.0027), slow ON (p=0.0036), and "uncertain” RGCs (p=0.014) was already reduced in rd10 compared to WT. Interestingly, at P180, a few responsive cells can still be detected, however, most of them display the functional profile of displaced amacrine cells.
Conclusions :
The plateau in responsiveness at P90 may hint at a possible rescue/rewiring effect, possibly due to atypical connections between the remaining photoreceptors and bipolar cells. In summary, our data argue against the loss of specific RGC channels during degeneration (at least until P90). Instead, decreasing input from photoreceptors is likely responsible for response loss across RGC types. Thus, our findings suggest that inner retinal circuits and visual feature extraction remain stable long after onset of rd10 photoreceptor degeneration, which has strong implications for vision restoration approaches.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.