Dopamine deficiency mediates early rod-driven inner retinal dysfunction in diabetic mice

• Type of Material: Article
• Authors: Moon K. Kim, Emory University; Moe H. Aung, Emory University; Lukas Mees, Georgia Institute of Technology; Darin Olson, Emory University; Nikita Pozdeyev, Emory University; P. Michael Iuvone, Emory University; Peter Martin Thule, Emory University; Machelle Pardue, Emory University
• Language: English
• Date: 2018-01-01
• Publisher: Association for Research in Vision and Ophthalmology (ARVO)
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1167/iovs.17-22692
• Title of Journal or Parent Work: Investigative Ophthalmology & Visual Science
• ISSN: 0146-0404
• Volume: 59
• Issue: 1
• Start Page: 572
• End Page: 581
• Grant/Funding Information: Supported by Department of Veterans Affairs Rehabilitation Research and Development Service (Merit Award I01RX2615 [MTP] and Research Career Scientist Award C9257S [MTP]) and Department of Veterans Affairs Biological Laboratory Research and Development Service Merit Award (PMT), Juvenile Diabetes Research Foundation Innovative Award (PMT), Research to Prevent Blindness (Department of Ophthalmology, Emory University), and National Institutes of Health R01 EY004864, P30 EY006360.
• Keywords: dopamine; oscillatory potentials; diabetic retinopathy; electroretinogram
• Research Categories: Health Sciences, Opthamology; Biology, Animal Physiology

Abstract

PURPOSE. Electroretinograms (ERGs) are abnormal in diabetic retinas before the appearance of vascular lesions, providing a possible biomarker for diabetic vision loss. Previously, we reported that decreased retinal dopamine (DA) levels in diabetic rodents contributed to early visual and retinal dysfunction. In the current study, we examined whether oscillatory potentials (OPs) could serve as a potential marker for detecting early inner retinal dysfunction due to retinal DA deficiency. METHODS. Retinal function was tested with dark-adapted ERGs, taken at 3, 4, and 5 weeks after diabetes induction with streptozotocin. Electrical responses were analyzed and correlations were made with previously reported retinal DA levels. The effect of restoring systemic DA levels or removing DA from the retina in diabetic mice on OPs was assessed using L-3,4-dihydroxyphenylalanine (L-DOPA) treatments and retina-specific tyrosine hydroxylase (Th) knockout mice (rTHKO), respectively. RESULTS. Diabetic animals had significantly delayed OPs compared to control animals in response to dim, but not bright, flash stimuli. L-DOPA treatment preserved OP implicit time in diabetic mice. Diabetic rTHKO mice had further delayed OPs compared to diabetic mice with normal retinal Th, with L-DOPA treatment also providing benefit. Decreasing retinal DA levels significantly correlated with increasing OP delays mediated by rod pathways. CONCLUSIONS. Our data suggest that inner retinal dysfunction in early-stage diabetes is mediated by rod-pathway deficits and DA deficiencies. OP delays may be used to determine the earliest functional deficits in diabetic retinopathy and to establish an early treatment window for DA therapies that may prevent progressive vision loss.