Abstract
Purpose :
Retinitis Pigmentosa (RP), the heterogeneous inherited disease, is a leading cause of blindness worldwide. In most cases, rod photoreceptors degenerate, followed by the secondary degeneration of cones. Although the mechanisms leading to secondary cone degeneration have been investigated earlier, strategies to promote cone survival are still lacking. Using a mouse model for the most common autosomal-dominant RP mutation of rhodopsin (P23H), bred without functional rods, we studied cone survival and function in RP.
Methods :
RhoP23H/WT mice were bred on Gnat1-knockout background (P23H Gnat1-/-) and were allowed to age up to 12 months. These mice lack rod mediated phototransduction. At 12 months, retinas were isolated, and their function was assessed using ex vivo electroretinogram (ERG) responses to light flashes, in the presence of barium. The cone photoreceptor response (a-wave) was recorded after blocking the signal transmission to ON bipolar cells using DL-AP4. The ON bipolar cell response (b-wave) was isolated by subtracting a-wave from the ERG response. The retinal structure was studied using optical coherence tomography (OCT) and immunohistochemistry. All comparisons were made between P23H mice of both sexes and their age-matched wildtype control littermates (n=3-5 per group).
Results :
In P23H Gnat1-/- mice, we observed sex differences in cone ERG responses. At 12 months, P23H Gnat1-/- males maintained cone function with a marginal reduction in their a-wave. However, in the females a-wave was significantly reduced (p=0.02) compared to WT littermates. The b-wave also was reduced in both male and female P23H Gnat1-/- mice compared to WT (NS). OCT imaging of the P23H Gnat1-/- retina revealed that, at 7 months outer nuclear layer (ONL) thickness is at ~ 50% of that of WT littermates.
Conclusions :
Our data show that cone function is maintained in older male P23H Gnat1-/- mice at least up to 1 year of age. The ONL thickness is less decreased in older male and female P23H Gnat1-/- mice, compared to published studies on P23H mice with functional rods. This suggests better survival of P23H rods in the absence of rod function. These data could lead to finding new strategies for prolonging cone survival in rod degenerating diseases.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.