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Georgia Perganta, Alun R. Barnard, Christiana Katti, Athanasios Vachtsevanos, Marcela Votruba, Robert E. MacLaren, Sumathi Sekaran; Light-driven Circadian Behaviours Are Preserved In Visually Impaired Opa1 Mutant Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2976.
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Autosomal dominant optic atrophy (ADOA) is the most common form of inherited optic neuropathy affecting predominantly the retinal ganglion cells (RGCs). Mutations in the optic atrophy 1 (OPA1) gene have been identified in most patients with ADOA. Visual deficits include reduced acuity, central visual field loss and colour vision defects. Mouse models of OPA1 ADOA also display RGC atrophy and visual dysfunction. Non-image-forming (NIF) visual behaviours including circadian photoentrainment have not been assessed in ADOA. These behaviours are driven by a subset of RGCs that express the photopigment melanopsin. We assessed light-driven circadian behaviours and melanopsin expression in the B6; C3-Opa1Q285STOP mouse model
Opa1+/+ and Opa1+/- mice were placed in cages equipped with a steel running wheel in a normal 12:12 hr light/dark (LD) cycle. Activity levels, length of the active phase and period were calculated. Negative masking (the suppression of activity by acute light) was assessed by exposure to a 3 hr light pulse at zeitgeber time (ZT) 14. Circadian phase shift responses were assessed following release into constant darkness. Mice were exposed to a 15-min monochromatic 480 nm or 525 nm phase shift pulse at circadian time (CT) 16. Immunohistochemistry in retinal flatmounts was used to assess melanopsin cell distribution and morphology. Melanopsin transcript levels was quantified by real-time quantitative PCR
Opa1 mutant mice exhibited normal entrainment to a 12:12 LD cycle, similar to wildtype controls. In response to a 3 hr masking light pulse, both wildtype and Opa1 mutant mice displayed a suppression in activity levels. Both genotypes displayed phase shift responses to monochromatic 480 or 525 nm pulses. There were no significant differences between Opa1+/+ and Opa1+/- data for any of the circadian behaviour tests. The number of melanopsin RGCs, cell morphology and melanopsin transcript levels were also not statisticically different between genotypes
The data suggest preservation of non-image-forming circadian behaviours in Opa1 mutant mice. These findings provide support to growing evidence suggesting increased resistance and survival of melanopsin-expressing RGCs in mitochondrial retinopathies.
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