Abstract
Purpose :
The RPE serves as the blood/retina barrier and facilitates removal of metabolic byproducts from the subretinal space to the choroid. Slc16a8 (Mct3) is an RPE-specific proton coupled monocarboxylate transporter responsible for lactate export identified by human genetic analyses to be associated with age-related macular degeneration (AMD). We investigated the loss of Slc16a8 under constant light exposure (CLE) conditions as a potential stress model, similar to that seen in aging patients, to gain new functional insights into AMD pathobiology.
Methods :
Mice with CRISPR mediated deletion of Slc16a8 were used to generate 10-week old Slc16a8-/- (n=6), Slc16a8+/- (n=13), and Slc16a8+/+ (n=8) mice. Full-field ERGs (150 cd*s/m2) were measured at baseline and after CLE to determine photoreceptor, bipolar, and RPE cell function using a-, b-, and c-wave amplitudes. OCT was measured at baseline and after CLE to evaluate retinal thickness. Mice were subjected to a CLE of 100k lux for 7 days to induce retinal degeneration.
Results :
At baseline (Fig. 1A), eyes from Slc16a8-/- mice had decreased a-, b-, and c-wave amplitudes compared to Slc16a8+/- and Slc16a8+/+ eyes (all p<0.0001). Eyes from Slc16a8+/- mice had decreased a- (p=0.0002) and c-waves (p=0.01) compared to Slc16a8+/+ eyes. No differences in retinal thickness between genotypes at baseline were found. After CLE, all eyes had decreased a- and b-waves (p<0.0001). Retinas from Slc16a8+/- and Slc16a8+/+ thinned after CLE (p<0.0001), but eyes from Slc16a8-/- slightly thickened (p=0.011). Eyes from Slc16a8+/-, but not Slc16a8-/-, mice showed more loss of a- and c-waves and more retinal thinning compared to eyes from Slc16a8+/+ mice (Fig. 1B, p=0.0002, 0.002, and <0.0001).
Conclusions :
Slc16a8 (Mct3) is necessary for retinal function, but does not affect retinal morphology prior to CLE. After CLE, eyes with complete loss of Slc16a8 do not have increased RPE cell dysfunction, but appear to have retinal edema, perhaps due to proton coupled lactate buildup. Mice with partial loss of Slc16a8 are prone to more photoreceptor and RPE cell dysfunction and more retinal thinning after CLE. These results show that Slc16a8 is key for proper retinal function, both before and after the CLE model of stress-induced retinal degeneration.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.