Effects of Glaucoma on the Circadian Timing System in Mice and Men

Abstract

Purpose: : Glaucoma is characterized by progressive, irreversible damage of the optic nerve and degenerative loss of retinal ganglion cells (RGC). However, the impact on melanopsin expressing RGCs (mRGCs) that regulate circadian responses to light remains controversial. We explored the anatomical, molecular and functional consequences of glaucoma on the circadian timing system in a rodent model of chronic ocular hypertension and in human patients with severe bilateral glaucoma.

Methods: : In rodents, the extent of degeneration of RGC and mRGC fiber projections was quantified using sensitive anterograde tracing and image-density analysis of axon terminals. Alteration of retinal opsins and ganglion cell markers was assayed using quantitative PCR. The capacity of animals to entrain locomotor activity to light was challenged using successive shifts of the light dark (LD) cycle associated with decreases in light intensity. In humans, the capacity of monochromatic light (500 nm) to suppress nocturnal plasma melatonin levels was studied in normal subjects and glaucomatous patients.

Results: : The quantity of RGC axons is reduced by 40-70% in all central visual structures, and notably in the SCN. Glaucomatous rats are able to entrain to the LD cycle at all light levels, but required more time to re-adjust activity to a shifted LD cycle and showed significantly greater variability in the timing of activity onsets. Q-PCR shows that melanopsin as well as rod and cone opsin mRNAs are significantly reduced in glaucomatous retinas. Human patients with severe bilateral glaucoma showed an attenuated suppression of melatonin by light and a high variability in the time of melatonin secretion onset (DLMO).

Conclusions: : Glaucoma affects central projections of all RGCs including mRGCs. In light of these results, the classical view of glaucoma as pathology unique to the visual system should be extended to include anatomical and functional alterations of the circadian timing system.

Keywords: circadian rhythms • ganglion cells • photoreceptors