Electroretinogram responses in myopia: a review

The stretching of a myopic eye is associated with several structural and functional changes in the retina and posterior segment of the eye. Recent research highlights the role of retinal signaling in ocular growth. Evidence from studies conducted on animal models and humans suggests that visual mechanisms regulating refractive development are primarily localized at the retina and that the visual signals from the retinal periphery are also critical for visually guided eye growth. Therefore, it is important to study the structural and functional changes in the retina in relation to refractive errors. This review will specifically focus on electroretinogram (ERG) changes in myopia and their implications in understanding the nature of retinal functioning in myopic eyes. Based on the available literature, we will discuss the fundamentals of retinal neurophysiology in the regulation of vision-dependent ocular growth, findings from various studies that investigated global and localized retinal functions in myopia using various types of ERGs.

Visually induced changes in cytokine production in the chick choroid

Postnatal ocular growth is regulated by a vision-dependent mechanism which acts to minimize refractive error through coordinated growth of the ocular tissues. Of great interest is the identification of the chemical signals that control visually-guided ocular growth. Here we provide evidence that the pro-inflammatory cytokine, Interleukin-6 (IL-6), may play a pivotal role in the control of ocular growth using a chicken model of myopia. Microarray, real time RT-qPCR, and ELISA analyses identified IL-6 upregulation in the choroids of chick eyes under two visual conditions that introduce myopic defocus and slow the rate of ocular elongation (recovery from induced myopia and compensation for positive lenses). Intraocular administration of atropine, an agent known to slow ocular elongation, also resulted in an increase in choroidal IL-6 gene expression. Nitric oxide appears to directly or indirectly upregulate choroidal IL-6 gene expression, as administration of the non-specific nitric oxide synthase inhibitor, L-NAME, inhibited choroidal IL-6 gene expression, and application of a nitric oxide donor stimulated IL-6 gene and protein expression in isolated chick choroids. Considering the pleiotropic nature of IL-6 and involvement in many biological processes, these results suggest that IL-6 may mediate many aspects of the choroidal response in the control of ocular growth.

Critical period for vision-dependent modulation of postnatal retinal neurogenesis

It is generally accepted that retinal neurogenesis in mammals ceases shortly after birth and that stem/progenitor cells found in the postnatal eyes of mice and humans are in the quiescent state. In the present study, we have investigated postnatal retinal neurogenesis and its modulation by visual experience in the mouse model. Four age groups (P26, P45, P72, and P94) of transgenic mice expressing green fluorescent protein (GFP) in the retinal progenitor cells under the control of nestin regulatory elements were examined for the presence of nestin-GFP-positive proliferating progenitor cells in the retina. Contrary to the previously held belief, we found a significant number of proliferating progenitors at the retinal periphery in all age groups examined. The majority of these cells gave rise to photoreceptors as revealed by the genetic cell fate mapping experiments. The intensity of neurogenesis was declining with age, and strongly correlated with eye growth. Visual form deprivation resulted in a significant increase in the intensity of peripheral neurogenesis, which correlated strongly with the induced ocular growth. The susceptibility to both form-deprivation-induced increase in the peripheral neurogenesis and form-deprivation-induced increase in the ocular growth declined with age ceasing completely around P70, which marked the end of the critical period for the vision-dependent modulation of both ocular growth and postnatal retinal neurogenesis. Thus, neurogenesis in the peripheral retina of young mice is modulated by visual input, but only during a critical period in postnatal development.

Visually Induced Changes in Cytokine Production in the Chick Choroid

Postnatal ocular growth is regulated by a vision-dependent mechanism which acts to minimize refractive error through coordinated growth of the ocular tissues. Of great interest is the identification of the chemical signals that control visually-guided ocular growth. Here we provide evidence that the pro-inflammatory cytokine, Interleukin-6 (IL-6), may play a pivotal role in the control of ocular growth using a chicken model of myopia. Microarray, real time RT-qPCR, and ELISA analyses identified IL-6 upregulation in the choroids of chick eyes under two visual conditions that introduce myopic defocus and slow the rate of ocular elongation (recovery from induced myopia and compensation for positive lenses). Intraocular administration of atropine, an agent known to slow ocular elongation, also resulted in an increase in choroidal IL-6 gene expression. Nitric oxide appears to directly or indirectly upregulate choroidal IL-6 gene expression, as administration of the non-specific nitric oxide synthase inhibitor, L-NAME, inhibited choroidal IL-6 gene expression, and application of a nitric oxide donor stimulated IL-6 gene and protein expression in isolated chick choroids. Considering the pleiotropic nature of IL- 6 and involvement in many biological processes, these results suggest that IL-6 may mediate many aspects of the choroidal response in the control of ocular growth.

Ocular growth and metabolomics are dependent upon the spectral content of ambient white light

Myopia results from an excessive axial growth of the eye, causing abnormal projection of remote images in front of the retina. Without adequate interventions, myopia is forecasted to affect 50% of the world population by 2050. Exposure to outdoor light plays a critical role in preventing myopia in children, possibly through the brightness and blue-shifted spectral composition of sunlight, which lacks in artificial indoor lighting. Here, we evaluated the impact of moderate levels of ambient standard white (SW: 233.1 lux, 3900 K) and blue-enriched white (BEW: 223.8 lux, 9700 K) lights on ocular growth and metabolomics in a chicken-model of form-deprivation myopia. Compared to SW light, BEW light decreased aberrant ocular axial elongation and accelerated recovery from form-deprivation. Furthermore, the metabolomic profiles in the vitreous and retinas of recovering form-deprived eyes were distinct from control eyes and were dependent on the spectral content of ambient light. For instance, exposure to BEW light was associated with deep lipid remodeling and metabolic changes related to energy production, cell proliferation, collagen turnover and nitric oxide metabolism. This study provides new insight on light-dependent modulations in ocular growth and metabolomics. If replicable in humans, our findings open new potential avenues for spectrally-tailored light-therapy strategies for myopia.

Identification of MFRP and the secreted serine proteases PRSS56 and ADAMTS19 as part of a molecular network involved in ocular growth regulation

Precise regulation of ocular size is a critical determinant of normal visual acuity. Although it is generally accepted that ocular growth relies on a cascade of signaling events transmitted from the retina to the sclera, the factors and mechanism(s) involved are poorly understood. Recent studies have highlighted the importance of the retinal secreted serine protease PRSS56 and transmembrane glycoprotein MFRP, a factor predominantly expressed in the retinal pigment epithelium (RPE), in ocular size determination. Mutations in PRSS56 and MFRP constitute a major cause of nanophthalmos, a condition characterized by severe reduction in ocular axial length/extreme hyperopia. Interestingly, common variants of these genes have been implicated in myopia, a condition associated with ocular elongation. Consistent with these findings, mice with loss of function mutation in PRSS56 or MFRP exhibit a reduction in ocular axial length. However, the molecular network and cellular processes involved in PRSS56- and MFRP-mediated ocular axial growth remain elusive. Here, we show that Adamts19 expression is significantly upregulated in the retina of mice lacking either Prss56 or Mfrp. Importantly, using genetic mouse models, we demonstrate that while ADAMTS19 is not required for ocular growth during normal development, its inactivation exacerbates ocular axial length reduction in Prss56 and Mfrp mutant mice. These results suggest that the upregulation of retinal Adamts19 is part of an adaptive molecular response to counteract impaired ocular growth. Using a complementary genetic approach, we show that loss of PRSS56 or MFRP function prevents excessive ocular axial growth in a mouse model of early-onset myopia caused by a null mutation in Irbp, thus, demonstrating that PRSS56 and MFRP are also required for pathological ocular elongation. Collectively, our findings provide new insights into the molecular network involved in ocular axial growth and support a role for molecular crosstalk between the retina and RPE involved in refractive development.

Light and myopia: from epidemiological studies to neurobiological mechanisms

Myopia is far beyond its inconvenience and represents a true, highly prevalent, sight-threatening ocular condition, especially in Asia. Without adequate interventions, the current epidemic of myopia is projected to affect 50% of the world population by 2050, becoming the leading cause of irreversible blindness. Although blurred vision, the predominant symptom of myopia, can be improved by contact lenses, glasses or refractive surgery, corrected myopia, particularly high myopia, still carries the risk of secondary blinding complications such as glaucoma, myopic maculopathy and retinal detachment, prompting the need for prevention. Epidemiological studies have reported an association between outdoor time and myopia prevention in children. The protective effect of time spent outdoors could be due to the unique characteristics (intensity, spectral distribution, temporal pattern, etc.) of sunlight that are lacking in artificial lighting. Concomitantly, studies in animal models have highlighted the efficacy of light and its components in delaying or even stopping the development of myopia and endeavoured to elucidate possible mechanisms involved in this process. In this narrative review, we (1) summarize the current knowledge concerning light modulation of ocular growth and refractive error development based on studies in human and animal models, (2) summarize potential neurobiological mechanisms involved in the effects of light on ocular growth and emmetropization and (3) highlight a potential pathway for the translational development of noninvasive light-therapy strategies for myopia prevention in children.

Effects of topical pilocarpine on ocular growth and refractive development in rabbits

Purpose: This study aimed to investigate whether topical pilocarpine affects ocular growth and refractive development as well as the underlying biochemical processes in early eye development in rabbits. Methods: Twenty three-week-old New Zealand white rabbits were treated with 0.5% pilocarpine in the right eye for 6 weeks. The left eyes served as contralateral controls. The effects of pilocarpine on refractive error, corneal curvature and ocular biometrics were assessed using streak retinoscopy, keratometry, and A-scan ultrasonography, respectively. Eyeballs were enucleated for histological analysis. The ciliary body and sclera were homogenized to determine the mRNA and protein expression levels of five subtypes of muscarinic receptors. Results: Compared to control eyes, pilocarpine-treated eyes exhibited approximately −1.63 ± 0.54 D myopia accompanied by a 0.11 ± 0.04 mm increase in axial length (AL) ( p < 0.001, respectively). The anterior chamber depth (ACD) was reduced, whereas the lens thickness (LT) and vitreous chamber depth (VCD) increased ( p < 0.001, respectively). Corneal curvature decreased over time but was not significantly different between treated and control eyes. The mRNA and protein expression levels of five subtypes of muscarinic receptors were upregulated in the ciliary body and downregulated in the sclera. Conclusions: Based on these results, pilocarpine can induce myopic shift, increase LT, elongate VCD and AL, and reduce muscarinic receptor expression in the sclera early in development. These changes raise the possibility that pilocarpine may promote axial elongation in ocular development and facilitate the emmetropization of hyperopic eyes.

Identification of ADAMTS19 as a novel retinal factor involved in ocular growth regulation

ABSTRACTRefractive errors are the most common ocular disorders and are a leading cause of visual impairment worldwide. Although ocular axial length is well established to be a major determinant of refractive errors, the molecular and cellular processes regulating ocular axial growth are poorly understood. Mutations in genes encoding the PRSS56 and MFRP are a major cause of nanophthalmos. Accordingly, mouse models with mutations in the genes encoding the retinal factor PRSS56 or MFRP, a gene predominantly localized in the retinal pigment epithelial (RPE) exhibit ocular axial length reduction and extreme hyperopia. However, the precise mechanisms underlying PRSS56- and MFRP-mediated ocular axial growth remain elusive. Here, we show that Adamts19 expression is significantly upregulated in retina of mice lacking either Prss56 or Mfrp. Using a combination of genetic approaches and mouse models, we show that while ADAMTS19 is not required for ocular growth during normal development, its inactivation exacerbates ocular axial length reduction in both Prss56 or Mfrp mutant mice. These results suggest that the upregulation of retinal Adamts19 expression is part of an adaptive molecular response to counteract impaired ocular growth. Using a complementary genetic approach. We further demonstrate that loss of PRSS56 or MFRP function prevents excessive ocular axial growth in a mouse model of developmental myopia caused by a null mutation in Irpb, demonstrating that ocular axial elongation in Irbp-/- mice is fully dependent on PRSS56 and MFRP functions. Collectively, our findings provide insight into the molecular network involved in ocular axial growth regulation and refractive development and support the notion that relay of the signal between the retina and RPE could be critical for promoting ocular axial elongation.