Abstract
Purpose :
RP59 is an autosomal recessive form of retinitis pigmentosa, which results in progressive, irreversible loss of vision. A K42E missense point mutation in the dehydrodolichyl diphosphate synthase (DHDDS) gene has been causally linked to RP59. DHDDS is required for synthesis of dolichol, which in turn is required for protein glycosylation, but the exact molecular mechanisms underlying RP59 pathogensis remain elusive. Here we further investigated the impact of homozygous K42E Dhdds mutation on visual function in a knock-in (KI) mouse model of RP59.
Methods :
Here, we used a novel K42E Dhdds KI mouse model as previously described. Surprisingly, these KI retinas exhibited normal histology from the birth up to 1 year old with no apparent signs of degeneration, however with extensive gliosis. To investigate the function of the KI retinas, we used electrophysiological and imaging methods to assess physiological properties of the whole retina and individual specialized retinal cells.
Results :
In vivo and ex vivo electroretinography (ERG) revealed normal light responses in the retina of young animals (2-4 months old). Older mice (11-14 months old) showed no changes in the ERG a-wave (photoreceptor responses) but a decrease in the amplitude of the b-wave (downstream circuitry). Single cell patch-clamp recordings from rod photoreceptors in retinal slices also demonstrated no changes in sensitivity and light response amplitudes. However, the downstream rod bipolar cells showed reduced sensitivity and amplitude. Another type of ON bipolar cells, ON-cone bipolar cells, demonstrated increased response amplitudes, while there was no difference in OFF-cone bipolar cells responses.
Conclusions :
Our results indicate a defect in the synaptic transmission at the first visual synapse between rods and bipolar cells in homozygous K42E Dhdds KI retinas.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.