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Gianluca Tosini, Coralie Gianesini, Susumu Hiragaki, Virginie Laurent, David Hicks; Cones Viability is Affected by Removal of Melatonin Signaling. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4249.
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© ARVO (1962-2015); The Authors (2016-present)
Previous studies have also demonstrated that melatonin may play an important role in the modulation of photoreceptors viability during aging and melatonin has been implicated in the pathogenesis of age-related macular degeneration. This hormone exerts its influence by binding to G-protein coupled receptors named melatonin receptor 1 (MT1) and 2 (MT2). MT1 and MT2 receptors activate a wide variety of signaling pathways and both receptors are present in the vertebrate photoreceptors where they form an MT1/MT2heteromers.
Melatonin proficient mice (C3H-f+/+) and melatonin proficient mice lacking MT1 or MT2 receptors (MT1-/- and MT2-/-) were used in this study. Mice were sacrificed at the age of 3, 12 and 18 months and photoreceptors viability was assessed by counting the number of nuclei in the outer nuclear layer and by counting the number of cones. Cones were identified by immunocytochemistry using peanut agglutinin lectin, green/red and blue opsin antibodies. AKT and FOXO1 were measured by western blotting and immunocytochemistry
The number of nuclei in the outer nuclear layer was significantly reduced in MT1-/- and MT2-/- mice at 18 months of age (P< 0.05) with respect to 3 months of age. We discovered that in 18 months old MT1-/- and MT2-/- mice the number of cones was significantly reduced with respect to young (3 months) MT1-/- and MT2-/- mice or age matched C3H-f+/+ .No difference in the number of cones in young C3H-f+/+, MT1-/- and MT2-/- mice (P> 0.1) or between young and old C3H-f+/+ mice (P > 0.1) was observed. The red/green cones showed a more pronounced decline than blue cones. In C3H-f+/+ the activation AKT-FOXO1 pathway showed a daily rhythm (P <0.05) with peak values at ZT22 and trough value at ZT1. No rhythmicity in the activation of AKT-FOXO1 was observed in MT1-/- and MT2-/- mice (P > 0.05). AKT/FOXO1 was localized in rods and cones.<br />
Our data indicate that removal of melatonin induces a significant reduction in the number of cell in the outer nuclear layer during aging. Surprisingly we found that the numbers ofred/green cones also declined with age in MT1-/- and MT2-/- mice. Our data also suggest that the AKT-FOXO1 survival pathway may be involved in the mechanism by which melatonin protect photoreceptors. Also in this case the action of melatonin on cone viability seems to be mediated by MT1/MT2 heteromers.
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