Melanopsin modulates refractive development and myopia

• Type of Material: Article
• Authors: Ranjay Chakraborty, Emory University; Erica G Landis, Emory University; Reece Mazade, Atlanta VA Health Care System; Victoria Yang, Atlanta VA Health Care System; Ryan Strickland, Atlanta VA Health Care System; Samer Hattar, NIMH, NIH, Rockville; Richard A Stone, University of Pennsylvania; Paul Iuvone, Emory University; Machelle Pardue, Emory University
• Language: English
• Date: 2021-12-01
• Publisher: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Published by Elsevier Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.exer.2021.108866
• Title of Journal or Parent Work: EXPERIMENTAL EYE RESEARCH
• Volume: 214
• Start Page: 108866
• End Page: 108866
• Grant/Funding Information: This project was supported by the National Institutes of Health [NIH R01 EY016435 (MTP), NIH R01 EY004864 and NIH R01 EY027711 (PMI), NIH R01 EY022342 (RAS), NIH P30 EY006360, T32 EY007092 (EGL)], Department of Veterans Affairs [Rehabilitation R&D Service Research Career Scientist Award IK6 RX003134 (MTP)], and Research to Prevent Blindness [Departmental Award]. The funding organizations had no role in the design or conducting of this research.
• Keywords: PHOTORECEPTORS; SUSCEPTIBILITY; L-3; OCULAR GROWTH; Life Sciences & Biomedicine; 4-dihydroxyphenylalanine (L-DOPA); VISUAL FUNCTION; DOPAMINE; Ophthalmology; 4-Dihydroxyphenylacetic acid (DOPAC); Dopamine; CIRCADIAN CLOCK; AGONIST; MOUSE MODEL; 3; Melanopsin retinal ganglion cells (mRGCs); RETINAL GANGLION-CELLS; Science & Technology; FORM-DEPRIVATION MYOPIA; Opn4

Abstract

Myopia, or nearsightedness, is the most common form of refractive abnormality and is characterized by excessive ocular elongation in relation to ocular power. Retinal neurotransmitter signaling, including dopamine, is implicated in myopic ocular growth, but the visual pathways that initiate and sustain myopia remain unclear. Melanopsin-expressing retinal ganglion cells (mRGCs), which detect light, are important for visual function, and have connections with retinal dopamine cells. Here, we investigated how mRGCs influence normal and myopic refractive development using two mutant mouse models: Opn4−/− mice that lack functional melanopsin photopigments and intrinsic mRGC responses but still receive other photoreceptor-mediated input to these cells; and Opn4DTA/DTA mice that lack intrinsic and photoreceptor-mediated mRGC responses due to mRGC cell death. In mice with intact vision or form-deprivation, we measured refractive error, ocular properties including axial length and corneal curvature, and the levels of retinal dopamine and its primary metabolite, L-3,4-dihydroxyphenylalanine (DOPAC). Myopia was measured as a myopic shift, or the difference in refractive error between the form-deprived and contralateral eyes. We found that Opn4−/− mice had altered normal refractive development compared to Opn4+/+ wildtype mice, starting ∼4D more myopic but developing ∼2D greater hyperopia by 16 weeks of age. Consistent with hyperopia at older ages, 16 week-old Opn4−/− mice also had shorter eyes compared to Opn4+/+ mice (3.34 vs 3.42 mm). Opn4DTA/DTA mice, however, were more hyperopic than both Opn4+/+ and Opn4−/− mice across development ending with even shorter axial lengths. Despite these differences, both Opn4−/− and Opn4DTA/DTA mice had ∼2D greater myopic shifts in response to form-deprivation compared to Opn4+/+ mice. Furthermore, when vision was intact, dopamine and DOPAC levels were similar between Opn4−/− and Opn4+/+ mice, but higher in Opn4DTA/DTA mice, which differed with age. However, form-deprivation reduced retinal dopamine and DOAPC by ∼20% in Opn4−/− compared to Opn4+/+ mice but did not affect retinal dopamine and DOPAC in Opn4DTA/DTA mice. Lastly, systemically treating Opn4−/− mice with the dopamine precursor L-DOPA reduced their form-deprivation myopia by half compared to non-treated mice. Collectively our findings show that disruption of retinal melanopsin signaling alters the rate and magnitude of normal refractive development, yields greater susceptibility to form-deprivation myopia, and changes dopamine signaling. Our results suggest that mRGCs participate in the eye's response to myopigenic stimuli, acting partly through dopaminergic mechanisms, and provide a potential therapeutic target underling myopia progression. We conclude that proper mRGC function is necessary for correct refractive development and protection from myopia progression.