Cone Viability Is Affected by Disruption of Melatonin Receptors Signaling

PURPOSE: Previous studies have demonstrated that melatonin has an important role in the modulation of photoreceptor viability during aging and may be involved in the pathogenesis of age-related macular degeneration.This hormone exerts its influence by binding to G-protein coupled receptors named melatonin receptor 1 (MT(1)) and 2 (MT(2)). Melatonin receptors 1 and 2 activate a wide variety of signaling pathways. METHODS: Melatonin-proficient mice (C3H/f(+/+)) and melatonin-proficient mice lacking MT(1) or MT(2) receptors (MT(1)(−/−) and MT(2)(−/−)) were used in this study. Mice were killed at the ages of 3 and 18 months, and photoreceptor viability was determined by counting nuclei number in the outer nuclear layer (ONL). Cones were identified by immunohistochemistry using peanut agglutinin (PNA) and green/red and blue opsin antibodies. Protein kinase B (AKT) and forkhead box O (FOXO1) were assessed by Western blotting and immunohistochemistry. RESULTS: The number of nuclei in the ONL was significantly reduced in C3Hf(+/+), MT(1)(−/−), and MT(2)(−/−) mice at 18 months of age with respect to 3-month-old animals. In 18-month-old MT(1)(−/−) and MT(2)(−/−) mice, but not in C3H/f(+/+), the number of cones was significantly reduced with respect to young MT(1)(−/−) and MT(2)(−/−) mice or age-matched C3H/f(+/+). In C3H/f(+/+), activation of the AKT-FOXO1 pathway in the photoreceptors showed a significant difference between night and day. CONCLUSIONS: Our data indicate that disruption of MT(1)/MT(2) heteromer signaling induces a reduction in the number of photoreceptors during aging and also suggest that the AKT-FOXO1 survival pathway may be involved in the mechanism by which melatonin protects photoreceptors.