Electroretinography and Gene Expression Measures Implicate Phototransduction and Metabolic Shifts in Chick Myopia and Hyperopia Models

Abstract

The Retinal Ion-Driven Fluid Efflux (RIDE) model theorizes that phototransduction-driven changes in trans-retinal ion and fluid transport underlie the development of myopia (short-sightedness). In support of this model, previous functional studies have identified the attenuation of outer retinal contributions to the global flash electroretinogram (gfERG) following weeks of myopia induction in chicks, while discovery-driven transcriptome studies have identified changes to the expression of ATP-driven ion transport and mitochondrial metabolism genes in the retina/RPE/choroid at the mid- to late-induction time-points. Less is known about the early time-points despite biometric analyses demonstrating changes in eye growth by 3 h in the chick lens defocus model. Thus, the present study compared gfERG and transcriptome profiles between 3 h and 3 days of negative lens-induced myopia and positive lens-induced hyperopia in chicks. Photoreceptor (a-wave and d-wave) and bipolar (b-wave and late-stage d-wave) cell responses were suppressed following negative lens-wear, particularly at the 3–4 h and 3-day time-points when active shifts in the rate of ocular growth were expected. Transcriptome measures revealed the up-regulation of oxidative phosphorylation genes following 6 h of negative lens-wear, concordant with previous reports at 2 days in this model. Signal transduction pathways, with core genes involved in glutamate and G-protein coupled receptor signalling, were down-regulated at 6 h. These findings contribute to a growing body of evidence for the dysregulation of phototransduction and mitochondrial metabolism in animal models of myopia.

Flash Electroretinography as a Measure of Retinal Function in Myopia and Hyperopia: A Systematic Review

“…The gfERG findings in human in human myopes reviewed here build on electrophysiological, structural, and pharmacological evidence from animal models implicating the photoreceptors and ON- and OFF- bipolar cell pathways in the control of eye growth and the development of myopia [ 18 , 19 , 20 , 57 ]. The human studies reviewed here consistently concur with the findings of gfERG studies in chick models of early and established myopia identifying decreased a-wave and b-wave amplitudes [ 36 , 37 , 38 , 39 ]. Using a quantitative model of phototransduction, Westbrook et al [ 39 ] derived the photoreceptor light response in myopic and emmetropic chick eyes from the leading edge of the a-wave.…”

“…The function of each cell type can be inferred by measuring the size of each wave (amplitude) and the difference in time between onset of the response and maximum response reached (implicit time). Consistent with the animal model pharmacological research outlined above, attenuation of the gfERG a-wave and b-wave amplitude has been demonstrated in studies of optically and pharmacologically induced myopia in chicks [ 36 , 37 , 38 , 39 ]. However, although gfERG has been used extensively in clinical settings to examine human myopia e.g., [ 40 , 41 , 42 , 43 , 44 ]; the findings have been mixed, and current knowledge has not been systematically reviewed.…”

Single‐cell RNA sequencing of retina revealed novel transcriptional landscape in high myopia and underlying cell‐type‐specific mechanisms

“…In this study, we revealed a shift toward OXPHOS in highly myopic photoreceptors. Similar metabolic alternations in myopic eyes have also been also mentioned in previous studies, which used bulk RNA sequencing of retinas 6,32 …”

“…reported that “abnormal photoreceptor inner segment morphology” was the most significant gene set enriched for myopia‐associated genes; other photoreceptor‐related gene sets include the “thin retinal outer nuclear layer”, “detection of light stimulus”, and “nonmotile primary cilium” 2 . Previous functional studies have also confirmed the attenuation of photoreceptor cell responses to flash electroretinography (a‐wave and d‐wave) in a murine model of myopia 6 . However, the underlying molecular mechanism was largely unknown.…”

“…Several genome‐wide association studies (GWAS) have also highlighted the essential roles of photosensitive and neuronal mechanisms underlying myopia progression 2–4 . Previous studies involving pharmacological inhibition of retinal neurotransmitters or genetic knockdown of cell‐type‐specific genes (e.g., Gnat1 −/− ) confirmed that a variety of retinal cell types might play roles in refractive development 5,6 . However, the retina is a complex tissue in which multiple heterogeneous cell types form complicated communication networks.…”