Developmental Progression of X-Linked Retinoschisis in Mouse Rods

Abstract

Purpose : X-linked Retinoschisis (XLRS) is an early onset degenerative retinal disease that causes cystic lesions in the middle layers of the retina, a loss of visual acuity, and decreased contrast sensitivity. XLRS is caused by mutations in Retinoschisin 1 (RS1) which encodes the secreted protein retinoschisin (RS1). Rs1-mutant mouse models develop key hallmarks of XLRS including intraretinal schisis and reduced ERG b-waves. The disease phenotype is present at early ages leading to the question of whether retinal development is ever normal. Here we explore the early ERG properties of Rs1 mutant mice, using an ex vivo system and pharmacological blockade to isolate ERG components generated by photoreceptors, depolarizing bipolar cells (DBCs) and Müller glial cells (MGCs).

Methods : We recorded light evoked responses from WT and two Rs1-mutant strains Rs1^KO, Rs1^C59S at P13, an age where Rs1 mutants have developed intraretinal schisis. After dark adaptation, mice were sacrificed and retinae were isolated and mounted on a custom ERG chamber. ERGs were evoked by 1-4 ms pulses from a LED band-passed at 505±20 nm in triplicate. Photon intensity was varied from 5-50,000 photons/um^-2. ERGs were recorded while retinae perfused by normal Ringers, Ringers contains barium chloride (100 µM) and then also LAP-4 (14 µM). Response components reflecting MGCs and DBCs were estimated by waveform subtraction.

Results : In comparison to WT, ERGs of Rs1 mutant mice had comparable b-waves, and a tendency toward larger a-waves, while MGC responses were only larger in Rs1^C59S mice.

Conclusions : These results indicate that Rs1 mutations have less impact on the rod pathway at P13 than at later ages. Ongoing studies will determine the ERG phenotype at still younger ages.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.