A spontaneous nonhuman primate model of myopic foveoschisis.

Abstract

Purpose : Myopic foveoschisis involves splitting of retinal layers at the fovea in highly myopic eyes which can resemble changes in X-linked retinoschisis (XLRS). Here, we characterize a novel nonhuman primate model of myopic foveoschisis by clinical exam, imaging, genetic, immunohistochemical, and single-nuclei transcriptomic analyses, focusing on retinoschisin 1 (RS1) – the extracellular retinal protein involved in maintaining retinal architecture and defective in XLRS.

Methods : We identified a 27-year-old rhesus macaque with visual behavior of myopia and performed ophthalmic examination with streak retinoscopy and biometry. Multimodal imaging including fundus photography (FP), fluorescein angiography (FA), and optical coherence tomography (OCT) was performed to monitor progression over 16 months prior to necropsy. Sanger sequencing was performed using human primers for RS1. Antibodies against rhodopsin, M/L opsin, GFAP, and Iba-1 were used to evaluate photoreceptors, macroglia, and microglia in the right eye. Single-nuclei RNA-sequencing (snRNA-seq) was performed on macular tissue for clustering, differentially expressed genes (DEGs), and pathway analyses.

Results : Ocular examination showed a prominent choroidal pattern and peripapillary atrophy suggestive of myopia, with mean refractive error of -13.5D and axial length of 21.5mm in the two eyes. FA showed no active choroidal neovascularization, but OCT revealed foveal schisis in outer plexiform layer (OPL) of the macula that worsened over time. Sanger sequencing showed no coding defects in the RS1 gene. Immunohistochemistry showed increased GFAP expression within Müller glia in the OPL, and loss of ramified Iba-1+ microglia, but no definite disruption of photoreceptors. SnRNA-seq of the macula showed transcriptionally-distinct cell types including rod, cone, bipolar, horizontal, amacrine, Müller, and ganglion cells that were similar in proportion to controls. Most retinal cell types showed predominantly upregulated DEGs, especially in cones. SnRNA-seq showed RS1 expression primarily in cones and rods that did not differ significantly from control eyes.

Conclusions : This spontaneous nonhuman primate model of myopic foveoschisis demonstrates a structural phenotype resembling XLRS with activated glial cells, but does not exhibit photoreceptor degeneration, RS1 mutation or changes in RS1 expression pattern, suggesting different molecular mechanisms between the two conditions.

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