title: Oxygen-induced retinopathy induces short-term glial stress and long-term impairment of photoentrainment in mice.
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.
authors: 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.
authors: Madah Khawn-I-Muhammad
authors: MK
authors: Mehdi
authors: Dominique
authors: D
authors: Sage-Ciocca
authors: Etienne
authors: E
authors: Challet
authors: André
authors: A
authors: Malan
authors: David
authors: D
authors: Hicks
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000473:pathology*; D015153:Blotting, Western; D002452:Cell Count; D002470:Cell Survival; D021081:Chronobiology Disorders / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018496:Hyperoxia / Q000150:complications*; D008027:Light; D051379:Mice; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010100:Oxygen / Q000633:toxicity; D011247:Pregnancy; D012162:Retinal Degeneration / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000502:physiology; D055351:Retinal Neurons / Q000473:pathology*; D012178:Retinopathy of Prematurity / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D017299:Rod Opsins / Q000378:metabolism; D000099210:Melanopsin
chemical_list: D009419:Nerve Tissue Proteins; D010100:Oxygen; D017299:Rod Opsins; D000099210:Melanopsin