Abstract
Purpose :
To investigate rod and cone contributions to the electroretinogram (ERG) of the RPE65-/- dog. Studies using double knockout mouse models showed that the residual ERG in RPE65-/- mice originates from desensitized rod function and not cones. In contrast, studies in human subjects showed that cones also contribute to the residual vision in RPE65 deficiency.
Methods :
RPE65-/- dogs have a desensitized ERG response. Young PDE6A-/- dogs lack rod function, revealing a cone-only ERG. Light-adapted ERGs from young PDE6A-/- (n=13), RPE65-/- (n=2), PDE6A-/-/RPE65-/- double knockout (n=4), and control (n=4) dogs were compared. Retinal cross-sectional morphology (spectral domain optical coherence tomography and histological sections) was compared.
Results :
Light-adapted ERGs from PDE6A-/- dogs, prior to cone degeneration, had relatively normal responses but with reduced a-wave amplitudes and delayed b-wave peak times. The age-matched RPE65-/- dogs showed elevated response thresholds, reduced a-wave amplitudes, and reduced b-wave amplitudes that increased to levels comparable to controls with increasing stimulus strength. The age-matched double knockout (cone-only function with a lack of 11-cis-retinal production) had a predominantly b-wave response with delayed peak times and decreased amplitudes, which increased with increasing stimulus strength, paralleling the RPE65-/- dog response. The ERG of the PDE6A-/- dogs progressively declined over 12-18 months. The double knockout had a more rapid ERG decline, while the RPE65-/- dog maintained responses. Retinal imaging showed a decrease in outer retinal thickness that occurred more rapidly in the double knockout compared to the PDE6A-/- dogs. Retinal histology at 9 months showed 1-2 rows of photoreceptor nuclei with prominent cone inner segments remaining in the PDE6A-/- dog, whereas the double knockout had 0-1 rows of photoreceptor nuclei and no discernable cone inner segments.
Conclusions :
The results from the double knockout dog suggest that the RPE65-/- dog light-adapted ERG has a predominant contribution from desensitized rods, but also a significant cone-mediated contribution. The lack of the classical visual cycle in RPE65-/- dogs is not compensated for by the alternative visual cycle supply of retinoid to cones in the double knockout dog. Lack of 11-cis-retinal accelerates the rate of photoreceptor degeneration in dogs with a progressive rod-led degeneration.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.