Modulation of the Daily Rhythm in Disc Shedding by Melatonin in the Mouse

Abstract

Purpose: Earlier studies in Xenopus have indicated a role for melatonin in the regulation of disc shedding, but the role of melatonin in the regulation of mammalian disc shedding is still unclear. This lack of data is due to the fact that the vast majority of mouse strains are genetically deficient in synthesizing melatonin in the pineal gland and retina, so very few studies have compared retinal physiology in melatonin-proficient and melatonin-deficient mice. We have recently produced a series of transgenic mice lacking melatonin receptor type 1 (MT1) or type 2 (MT2) in a melatonin proficient background (C3H-f+\+) and we have shown that removal of MT1 and MT2 receptors produces significant effects on photoreceptor physiology and on the daily and circadian regulation of photoreceptor functions.

Methods: Melatonin proficient mice and melatonin proficient mice lacking MT1 or MT2 receptors were used in this study. The rhythm in disc shedding was measured by counting the number of phagosomes at 3 hrs. intervals during the day. Lipofuscin levels and morphometric analysis of retinal sections were determined by light microscopy Changes in the mRNA levels of clock genes over the course of the day were determined by Real-time quantitative PCR.

Results: Our data indicate that removal of melatonin receptors induced significant changes in timing of the daily rhythm since in MT1 and MT2 knock-out mice the peak were advanced by 3 hours and occurred in dark instead than after the onset of light. This small change in the timing of the daily rhythms in phagocytosis seems to produce a significant effect on retinal and retinal pigmented epithelium (RPE) health since MT1 and MT2 knock-out mice showed a significant increase in lipofuscin accumulation in the RPE and a significant reduction in the number of photoreceptor cells during aging.

Conclusions: Our data indicate that removal of melatonin signaling perturbs the timing of the daily peak in phagocytosis. Such a change appears to negatively affect the overall health of the retina and RPE. We are now investigating the effects produced by removal of melatonin signaling on the molecular mechanisms that regulate this rhythm.

Keywords: 458 circadian rhythms • 590 melatonin • 701 retinal pigment epithelium