Expression of lactate transporters in the RPE and photoreceptors is required for health and functional activity of the outer retina.

Abstract

Purpose : Glucose is the primary energy substrate of the outer retina, which is metabolized through aerobic glycolysis generating large amounts of lactate. The lactate provides metabolic substrate for the RPE, so glucose is spared for the outer retina. Proton-coupled monocarboxylate transporters (MCTs) that transport lactate into and out of cells require an accessory protein Bsg for maturation and trafficking to the plasma membrane. Previous studies demonstrated Bsg^-/- mice have early loss of rod and cone function, followed by progressive photoreceptor cell death. In this study, we deleted Bsg in a cell-specific fashion from the RPE and rod photoreceptors to better understand how MCTs support retinal function.

Methods : Mice carrying floxed alleles for Bsg (Bsg^Flox/Flox) were crossed with Cre transgenic lines that target RPE (RPEΔBsg) or rods (RodΔBsg). Retinal structure and function were assessed in Bsg^Flox/Flox Cre transgenic mice and control littermates by optical coherence tomography (OCT), scanning laser ophthalmoscopy (SLO) and electroretinograms (ERGs). Eyes were subsequently studies using histological, immunofluorescence, and biochemical techniques.

Results : OCT imaging of RPEΔBsg mice showed a thinning of the outer nuclear layer with age and an increase in thickness of the subretinal space. SLO imaging showed a progressive accumulation of hyperflourescent particles in the retina that were found by histological analysis to correlate with loss of RPE from the basal lamina and migration of RPE cells into the subretinal space. ERG amplitudes were progressively reduced with age to an extent that correlated with the extent of the Bsg deletion in the RPE. In RodΔBsg mice, the outer nuclear layer thinned with age, to ~50% of control at 9 months of age. Scotopic ERGs were progressively reduced in these animals while cone ERGs retained a normal amplitude. RodΔBsg mice had reduced MCT protein expression but lactate efflux from isolated retinas was comparable to controls.

Conclusions : Cell-specific deletion of Bsg clarifies the different contributions of the RPE and rods to the systemic Bsg knock-out and underscore the importance of MCTs and the lactate shuttle in the outer retina.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.