Glaucoma Alters the Circadian Timing System

Abstract

Glaucoma is a widespread ocular disease and major cause of blindness characterized by progressive, irreversible damage of the optic nerve. Although the degenerative loss of retinal ganglion cells (RGC) and visual deficits associated with glaucoma have been extensively studied, we hypothesize that glaucoma will also lead to alteration of the circadian timing system. Circadian and non-visual responses to light are mediated by a specialized subset of melanopsin expressing RGCs that provide photic input to mammalian endogenous clock in the suprachiasmatic nucleus (SCN). In order to explore the molecular, anatomical and functional consequences of glaucoma we used a rodent model of chronic ocular hypertension, a primary causal factor of the pathology. Quantitative analysis of retinal projections using sensitive anterograde tracing demonstrates a significant reduction (∼50–70%) of RGC axon terminals in all visual and non-visual structures and notably in the SCN. The capacity of glaucomatous rats to entrain to light was challenged by exposure to successive shifts of the light dark (LD) cycle associated with step-wise decreases in light intensity. Although glaucomatous rats are able to entrain their locomotor activity to the LD cycle at all light levels, they require more time to re-adjust to a shifted LD cycle and show significantly greater variability in activity onsets in comparison with normal rats. Quantitative PCR reveals the novel finding that melanopsin as well as rod and cone opsin mRNAs are significantly reduced in glaucomatous retinas. Our findings demonstrate that glaucoma impacts on all these aspects of the circadian timing system. 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.

Distal axonopathy with structural persistence in glaucomatous neurodegeneration

“…We used 2.5% isoflurane anesthesia for intravitreal injection of 1 μL (mice) or 2 μL (rats) of CTB conjugated to Alexa Fluor-488 or -594 (1 μL of 1% CTB in sterile PBS solution; Invitrogen) using a glass pipette (50-μm tip). CTB is an established marker for active uptake and transport and has been used successfully to assess the retinal projection to the SC in injury (21,22,45). Animals were transcardially perfused with 4% paraformaldehyde in PBS solution and tissues removed after 48 h of CTB activity, an established period for complete retinotopic mapping of the SC for mice and other small mammals (28).…”

Intrinsically Photosensitive Retinal Ganglion Cells

“…Melanopsin-expressing RGCs were found to be selectively spared compared to conventional RGCs in a rat model of chronic ocular hypertension induced by laser photocoagulation of the episcleral and limbal veins P h y s i o l B i o c h e m P h a R m a c o l 1 6 2 ( 2 0 1 2 ) of the eye with resultant elevated intraocular pressure (IOP) (Li et al 2006(Li et al , 2008. In a different rat model of episcleral vein cauterization, melanopsin-expression RGCs were not apparently spared (Drouyer et al 2008;Wang et al 2008) and functional deficits in irradiance responses were reported (Drouyer et al 2008). In a rat glaucoma model of chronic ocular hypertension induced by weekly injections of chondroitin sulfate into the anterior chamber, melanopsinexpressing RGCs were also found to be equally susceptible to the deleterious effects of ocular hypertension and functional deficits in irradiance responses were also described (de Zavalia et al 2011).…”

The retinal clock in mammals: role in health and disease

“…112 In addition, several nonvisual responses to light were affected, such as the pupillary light response, light-induced nocturnal pineal melatonin suppression, and locomotor activity rhythm. 106,108 Dysfunction of ipRGCs in animal models of glaucoma have been corroborated by human studies because glaucoma patients with sleep disorders showed a reduction in the pupillary light response and suppression of nocturnal melatonin by light. [113][114][115][116][117][118] The potential role of ipRGCs has been described in other pathological processes.…”

“…105 The classic hallmark of glaucomatous optic neuropathies is the progressive loss of RGCs and their axons, with concomitant insidious defects in the visual field. As for RGCs, ipRGC abnormalities have been reported in rodent models of experimental glaucoma [106][107][108][109] and in glaucomatous patients. 110,111 We reported an ~50%-70% reduction of RGC axon terminals (including ipRGCs) in several visual and nonvisual structures, notably in the SCN, and an alteration of the expression of opsin genes in the retina in an experimental rat model of glaucoma, 106 as observed by others.…”

“…As for RGCs, ipRGC abnormalities have been reported in rodent models of experimental glaucoma [106][107][108][109] and in glaucomatous patients. 110,111 We reported an ~50%-70% reduction of RGC axon terminals (including ipRGCs) in several visual and nonvisual structures, notably in the SCN, and an alteration of the expression of opsin genes in the retina in an experimental rat model of glaucoma, 106 as observed by others. 112 In addition, several nonvisual responses to light were affected, such as the pupillary light response, light-induced nocturnal pineal melatonin suppression, and locomotor activity rhythm.…”