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Oxygen-induced retinopathy induces short-term glial stress and long-term impairment of photoentrainment in mice

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Abstract

Background

Retinopathy of prematurity is a serious potentially blinding disease of pre-term infants. There is extensive vascular remodeling and tissue stress, but data concerning alterations in retinal neurons and glia, and long-term functional sequelae are still incomplete.

Methods

ROP was induced using the oxygen-induced retinopathy (OIR) mouse model. Postnatal day 7 (P7) 129SVE mice were exposed to hyperoxia (75 ± 0.5 % oxygen) for 5 days, and then returned to normoxia to induce OIR. Exposed animals were euthanized at 5 (P17-OIR) and 14 days (P26-OIR) after return to normal air, together with corresponding age-matched control mice (P17-C and P26-C respectively) raised only in room air. Their retinas were examined by immunohistochemistry using a battery of antibodies against key glial and neuronal proteins. A further group of OIR mice and controls were examined at 10 weeks of age for their ability to re-entrain to changing 12 h light/12 h dark cycles, assayed by wheel-running actimetry. In this protocol, animals were subjected to three successive conditions of 300 lux, 15 lux and 1 lux ambient light intensity coupled with 6 hours of jetlag. Animals were euthanized at 4 months of age and used in immunoblotting for rhodopsin.

Results

Compared to P17-C, immunohistochemical staining of P17-OIR sections showed up-regulation of stress-related and glutamate-regulatory proteins in astrocytes and Müller glial cells. In contrast, glial phenotypic expression in P26-OIR retinas largely resembled that in P26-C. There was no loss in total retinal ganglion cells (RGC) at either P17-OIR or P26-OIR compared to corresponding controls, whereas intrinsically photosensitive RGC showed significant decreases, with 375 ± 13/field in P26-OIR compared to 443 ± 30/field in P26-C (p < 0.05). Wheel actimetry performed on control and OIR-treated mice at 4 months demonstrated that animals raised in hyperoxic conditions had impaired photoentrainment at low illuminance of 1 lux, as well as significantly reduced levels of rhodopsin compared to age-matched controls.

Conclusions

OIR leads to transient up-regulation of retinal glial proteins involved in metabolism, and partial degeneration of intrinsically photosensitive RGC and rod photoreceptors. OIR affects circadian photo-entrainment at low illuminance values, possibly by affecting the rod pathway and/or intrinsically photosensitive RGC input to the circadian clock. This study hence shows that retinopathy of prematurity affects light-regulated circadian behavior in an animal model, and may induce similar problems in humans.

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Acknowledgments

We are thankful to Dr L. Smith for her personal guidance on the choice of our animal model. We are grateful to Dr J. Mendoza for his valuable input in the analysis of actograms and statistical data. Our work was supported by a doctoral fellowship from the Higher Education Commission (HEC) of Pakistan.

Conflict of interest

The authors declare no conflict of interest in the making of these experiments, and did not receive any financial assistance other than grant support to MM and DH.

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Authors and Affiliations

  1. Département de Neurobiologie des Rythmes, Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212 Université de Strasbourg, 5 rue Blaise Pascal, 67084, Strasbourg, Cedex, France

    Madah Khawn -i- Muhammad Mehdi, Etienne Challet, André Malan & David Hicks

  2. Chronobiotron, UMS3415, CNRS and University of Strasbourg, Strasbourg, France

    Dominique Sage-Ciocca

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  1. Madah Khawn -i- Muhammad Mehdi
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Correspondence to David Hicks.

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The authors have full control of all primary data, and they agree to allow Graefe's Archive for Clinical and Experimental Ophthalmology to review their data upon request.

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Mehdi, M.K.i.M., Sage-Ciocca, D., Challet, E. et al. Oxygen-induced retinopathy induces short-term glial stress and long-term impairment of photoentrainment in mice. Graefes Arch Clin Exp Ophthalmol 252, 595–608 (2014). https://doi.org/10.1007/s00417-014-2579-5

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  • DOI: https://doi.org/10.1007/s00417-014-2579-5

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