Involvement of GABA Transporters
in Atropine-Treated
Myopic Retina As Revealed by iTRAQ Quantitative Proteomics

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Abstract

Atropine, a muscarinic antagonist, is known to inhibit myopia progression in several animal models and humans. However, the mode of action is not established yet. In this study, we compared quantitative iTRAQ proteomic analysis in the retinas collected from control and lens-induced myopic (LIM) mouse eyes treated with atropine. The myopic group received a (−15D) spectacle lens over the right eye on postnatal day 10 with or without atropine eye drops starting on postnatal day 24. Axial length was measured by optical low coherence interferometry (OLCI), AC-Master, and refraction was measured by automated infrared photorefractor at postnatal 24, 38, and 52 days. Retinal tissue samples were pooled from six eyes for each group. The experiments were repeated twice, and technical replicates were also performed for liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis. MetaCore was used to perform protein profiling for pathway analysis. We identified a total of 3882 unique proteins with <1% FDR by analyzing the samples in replicates for two independent experiments. This is the largest number of mouse retina proteome reported to date. Thirty proteins were found to be up-regulated (ratio for myopia/control > global mean ratio + 1 standard deviation), and 28 proteins were down-regulated (ratio for myopia/control < global mean ratio - 1 standard deviation) in myopic eyes as compared with control retinas. Pathway analysis using MetaCore revealed regulation of γ-aminobutyric acid (GABA) levels in the myopic eyes. Detailed analysis of the quantitative proteomics data showed that the levels of GABA transporter 1 (GAT-1) were elevated in myopic retina and significantly reduced after atropine treatment. These results were further validated with immunohistochemistry and Western blot analysis. In conclusion, this study provides a comprehensive quantitative proteomic analysis of atropine-treated mouse retina and suggests the involvement of GABAergic signaling in the antimyopic effects of atropine in mouse eyes. The GABAergic transmission in the neural retina plays a pivotal role in the maintenance of axial eye growth in mammals.

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Most cited references 58

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Atropine for the treatment of childhood myopia.

Yvonne Ling, Han Chow Chua, Boon Quah … (2006)

To evaluate the efficacy and safety of topical atropine, a nonselective muscarinic antagonist, in slowing the progression of myopia and ocular axial elongation in Asian children. Parallel-group, placebo-controlled, randomized, double-masked study. Four hundred children aged 6 to 12 years with refractive error of spherical equivalent -1.00 to -6.00 diopters (D) and astigmatism of -1.50 D or less. Participants were assigned with equal probability to receive either 1% atropine or vehicle eye drops once nightly for 2 years. Only 1 eye of each subject was chosen through randomization for treatment. The main efficacy outcome measures were change in spherical equivalent refraction as measured by cycloplegic autorefraction and change in ocular axial length as measured by ultrasonography. The primary safety outcome measure was the occurrence of adverse events. Three hundred forty-six (86.5%) children completed the 2-year study. After 2 years, the mean progression of myopia and of axial elongation in the placebo-treated control eyes was -1.20+/-0.69 D and 0.38+/-0.38 mm, respectively. In the atropine-treated eyes, myopia progression was only -0.28+/-0.92 D, whereas the axial length remained essentially unchanged compared with baseline (-0.02+/-0.35 mm). The differences in myopia progression and axial elongation between the 2 groups were -0.92 D (95% confidence interval, -1.10 to -0.77 D; P<0.001) and 0.40 mm (95% confidence interval, 0.35-0.45 mm; P<0.001), respectively. No serious adverse events related to atropine were reported. Topical atropine was well tolerated and effective in slowing the progression of low and moderate myopia and ocular axial elongation in Asian children.

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An updated view on the role of dopamine in myopia.

Marita Feldkaemper, Frank Schaeffel (2013)

A large body of data is available to support the hypothesis that dopamine (DA) is one of the retinal neurotransmitters involved in the signaling cascade that controls eye growth by vision. Initially, reduced retinal DA levels were observed in eyes deprived of sharp vision by either diffusers ("deprivation myopia", DM) or negative lenses ("lens induced myopia", LIM). Simulating high retinal DA levels by intravitreal application of a DA agonist can suppress the development of both DM and LIM. Also more recent studies using knock-out mouse models of DA receptors support the idea of an association between decreased DA levels and DM. There seem to be differences in the magnitude of the effects of DA on DM and LIM, with larger changes in DM but the degrees of image degradation by both treatments need to be matched to support this conclusion. Although a number of studies have shown that the inhibitory effects of dopamine agonists on DM and LIM are mediated through stimulation of the D2-receptor, there is also recent evidence that the balance of D2- and D1-receptor activation is important. Inhibition of D2-receptors can also slow the development of spontaneous myopia in albino guinea pigs. Retinal DA content displays a distinct endogenous diurnal, and partially circadian rhythm. In addition, retinal DA is regulated by a number of visual stimuli like retinal illuminance, spatial frequency content of the image, temporal contrast and, in chicks, by the light input from the pineal organ. A close interaction was found between muscarinergic and dopaminergic systems, and between nitric oxide and dopaminergic pathways, and there is evidence for crosstalk between the different pathways, perhaps multiple binding of the ligands to different receptors. It was shown that DA agonists interact with the immediate early signaling molecule ZENK which triggers the first steps in eye growth regulation. However, since long treatment periods were often needed to induce significant changes in retinal dopamine synthesis and release, the role of dopamine in the early steps is unclear. The wide spatial distribution of dopaminergic amacrine cells in the retina and the observation that changes in dopamine levels can be locally induced by local retinal deprivation is in line with the assumption that dopaminergic mechanisms control both central and peripheral eye growth. The protective effect of outdoor activity on myopia development in children seems to be partly mediated by the stimulatory effect of light on retinal dopamine production and release. However, the dose-response function linking light exposure to dopamine and to the suppression of myopia is not known and requires further studies.

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Specific GABAA circuits for visual cortical plasticity.

K Low, Jean-Marc Fritschy, Takao Hensch … (2004)

Weak inhibition within visual cortex early in life prevents experience-dependent plasticity. Loss of responsiveness to an eye deprived of vision can be initiated prematurely by enhancing gamma-aminobutyric acid (GABA)-mediated transmission with benzodiazepines. Here, we use a mouse "knockin" mutation to alpha subunits that renders individual GABA type A (GABA(A)) receptors insensitive to diazepam to show that a particular inhibitory network controls expression of the critical period. Only alpha1-containing circuits were found to drive cortical plasticity, whereas alpha2-enriched connections separately regulated neuronal firing. This dissociation carries implications for models of brain development and the safe design of benzodiazepines for use in infants.

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Author and article information

Journal

Journal ID (nlm-ta): J Proteome Res

Journal ID (iso-abbrev): J. Proteome Res

Journal ID (publisher-id): pr

Journal ID (coden): jprobs

Title: Journal of Proteome Research

Publisher: American Chemical Society

ISSN (Print): 1535-3893

ISSN (Electronic): 1535-3907

Publication date PMC-release: 11 September 2015

Publication date (Electronic): 11 September 2014

Publication date (Print): 07 November 2014

Volume: 13

Issue: 11 , Proteomics of Human Diseases: Pathogenesis, Diagnosis, Prognosis, and Treatment

Pages: 4647-4658

Affiliations

[† ]Singapore Eye Research Institute , 11 Third Hospital Avenue, Singapore 168751, Singapore

[‡ ]Dept. of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore , 5 Lower Kent Ridge Road, Singapore 119074, Singapore

[§ ]SRP Neuroscience and Behavioral Disorder, DUKE-NUS Graduate Medical School , 8 College Road, Singapore 169857, Singapore

[∥ ]Singapore Immunology Network, A*Star , 8a Biomedical Grove, Singapore 138648, Singapore

[⊥ ]Department of Statistics and Applied Probability, National University of Singapore , 6 Science Drive 2, Singapore 117546, Singapore

[ # ]Departments of Ophthalmology and Pharmacology, Emory University School of Medicine , 1365B Clifton Road NE, Atlanta, Georgia 30322, United States

Author notes

[* ]E-mail: zhou.lei@ 123456seri.com.sg . Tel: + (65) 63224546. Fax: + (65) 63224599.

Article

DOI: 10.1021/pr500558y

PMC ID: 4227558

PubMed ID: 25211393

SO-VID: 643944fd-fcec-481a-9aaa-75104e35f43b

License:

This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

History

Date received : 06 June 2014

Funding

National Institutes of Health, United States

Custom metadata

document-id-old-9 pr500558y

document-id-new-14 pr-2014-00558y

ccc-price

ScienceOpen disciplines: Molecular biology

Keywords: retina proteomics,itraq,quantitative proteomics,myopia,lens-induced myopia mouse model

Data availability:

ScienceOpen disciplines: Molecular biology

Keywords: retina proteomics, itraq, quantitative proteomics, myopia, lens-induced myopia mouse model

Involvement of GABA Transporters in Atropine-Treated Myopic Retina As Revealed by iTRAQ Quantitative Proteomics

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Abstract

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Higher order chromatin architecture

Most cited references 58

Atropine for the treatment of childhood myopia.

An updated view on the role of dopamine in myopia.

Specific GABAA circuits for visual cortical plasticity.

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Affiliations

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