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 (MT1) and 2 (MT2). Melatonin receptors 1 and 2 activate a wide variety of signaling pathways.

METHODS

Melatonin-proficient mice (C3H/f+/+) and melatonin-proficient mice lacking MT1 or MT2 receptors (MT1-/- and MT2-/-) 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+/+, MT1-/-, and MT2-/- mice at 18 months of age with respect to 3-month-old animals. In 18-month-old MT1-/- and MT2-/- mice, but not in C3H/f+/+, the number of cones was significantly reduced with respect to young MT1-/- and MT2-/- 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 MT1/MT2 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.