Inner retinal degeneration in Opa1 haploinsufficient mouse

Abstract

Purpose : OPA1 is a gene regulating mitochondrial fusion and matching energy supply and demand. In humans, mutation in the OPA1 gene causes Autosomal Dominant Optic Atrophy (ADOA). The haploinsufficiency mouse, B6;C3-Opa1^Q285STOP , displays a range of mitochondrial cellular abnormalities, with an apparently normal phenotype up to 10 months of age, after which it develops progressive visual and cognitive deficits. The purpose of this study was to define the inner retinal changes in aged Opa1^Q285X mice.

Methods : We imaged the central retina in both eyes of seven wild type and seven aged Opa1^Q285X mice (20+ months). All experiments were undertaken in accordance with the UK Animals (Scientific Procedures) Act and the Association for Research in Vision and Ophthalmology guidelines for the use of animals in research. OCT images were acquired with Phoenix Retinal Imaging System (Phoenix Research Labs, CA, USA). Five 3D images per eye were acquired in five locations (optic disk, temporal, nasal, superior and interior quadrants). Each image volume was 512x512x1024 voxels with resolution of 0.79x0.48x1um. Images were re-aligned in a 3D stack to compensate for respiratory and cardiac movements (Stack Reg, Translation, ImageJ) and analysed with InSight3D (Voxeleron, CA, USA) murine retinal layer segmentation software distributed. Immunohistochemistry was carried out on retinal sections by standard techniques.

Results : Our data revealed disrupted glia and blood supply in the retinal nerve fibre layer (RNFL) in both groups, with abnormalities more severe in mutant retina resulting in visible differences in layer thickness. Retinal ganglion cell (RGC) dendropathy, documented in this model and expected to affect the inner plexiform layer (IPL), could be detected by texture analyses of OCT images. IPL thickness measures were variable and were affected by non-inflammatory retinal swelling and liquid accumulation. We found only small region-specific difference in the thickness of the IPL. Our histological observations suggest depletion of native glia and microglia populations and recruitment of external cells.

Conclusions : We found deterioration of RNFL and CGL in temporal and superior quadrants without significant changes in IPL layer thickness. We hypothesise that gliosis may compensate for the loss of RGC dendrites.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.