Spatio-temporal characterization of S- and M/L-cone degeneration in the Rd1 mouse model of retinitis pigmentosa.

BACKGROUND: The Pde6brd1 (Rd1) mouse is widely used as a murine model for human retinitis pigmentosa. Understanding the spatio-temporal patterns of cone degeneration is important for evaluating potential treatments. In the present study we performed a systematic characterization of the spatio-temporal patterns of S- and M/L-opsin+ cone outer segment and cell body degeneration in Rd1 mice, described the distribution and proportion of dual cones in Rd1 retinas, and examined the kinetics of microglial activation during the period of cone degeneration. RESULTS: Outer segments of S- and M/L-cones degenerated far more rapidly than their somas. Loss of both S- and M/L-opsin+ outer segments was fundamentally complete by P21 in the central retina, and 90% complete by P45 in the peripheral retina. In comparison, degeneration of S- and M/L-opsin+ cell bodies proceeded at a slower rate. There was a marked hemispheric asymmetry in the rate of S-opsin+ and M/L-opsin+ cell body degeneration. M/L-opsin+ cones were more resilient to degeneration in the superior retina, whilst S-opsin+ cones were relatively preserved in the inferior retina. In addition, cone outer segment and cell body degeneration occurred far more rapidly in the central than the peripheral retina. At P14, the superior retina comprised a minority of genuine S-cones with a much greater complement of genuine M/L-opsin cones and dual cones, whilst the other three retinal quadrants had broadly similar numbers of genuine S-cones, genuine M/L-cones and dual cones. At P60, approximately 50% of surviving cones in the superior, nasal and temporal quadrants were dual cones. In contrast, the inferior peripheral retina at P60 contained almost exclusively genuine S-cones with a tiny minority of dual cones. Microglial number and activity were stimulated during rod breakdown, remained relatively high during cone outer segment degeneration and loss of cone somas in the central retina, and decreased thereafter in the period coincident with slow degeneration of cone cell bodies in the peripheral retina. CONCLUSION: The results of the present study provide valuable insights into cone degeneration in the Rd1 mouse, substantiating and extending conclusions drawn from earlier studies.

Glucose metabolism in mammalian photoreceptor inner and outer segments.

Photoreceptors are the first-order neurons of the visual pathway, converting light into electrical signals. Rods and cones are the two main types of photoreceptors in the mammalian retina. Rods are specialized for sensitivity at the expense of resolution and are responsible for vision in dimly lit conditions. Cones are responsible for high acuity central vision and colour vision. Many human retinal diseases are characterized by a progressive loss of photoreceptors. Photoreceptors consist of four primary regions: outer segments, inner segments, cell bodies and synaptic terminals. Photoreceptors consume large amounts of energy, and therefore, energy metabolism may be a critical juncture that links photoreceptor function and survival. Cones require more energy than rods, and cone degeneration is the main cause of clinically significant vision loss in retinal diseases. Photoreceptor segments are capable of utilizing various energy substrates, including glucose, to meet their large energy demands. The pathways by which photoreceptor segments meet their energy demands remain incompletely understood. Improvements in the understanding of glucose metabolism in photoreceptor segments may provide insight into the reasons why photoreceptors degenerate due to energy failure. This may, in turn, assist in developing bio-energetic therapies aimed at protecting photoreceptors.

Immune priming and experimental glaucoma: the effect of prior systemic lipopolysaccharide challenge on tissue outcomes after optic nerve injury.

BACKGROUND: Microglial activation is a prominent feature throughout the optic pathway in experimental glaucoma. Pro-inflammatory microglial activation may contribute to neurodegeneration through the release of pro-inflammatory cytokines and other inflammatory mediators. Systemic administration of lipopolysaccharide stimulates microglia to produce pro-inflammatory cytokines and chemoattractants. A preliminary investigation demonstrated pro-inflammatory microglial activation throughout the optic pathway following systemic lipopolysaccharide challenge. The aim of the current work was to investigate whether microglial priming with lipopolysaccharide would exacerbate optic nerve injury in rats following experimental glaucoma. METHODS: Adult female Sprague-Dawley rats were divided into lipopolysaccharide treatment (n = 15) and saline treatment groups (n = 15). Microglial priming was induced with a 2.5-mg/kg intraperitoneal injection of lipopolysaccharide; control animals received saline. Experimental glaucoma was induced 48 h later in the right eyes of animals by laser photocoagulation of the trabecular meshwork. Animals were sacrificed 9 days after laser treatment. RESULTS: The estimated number of axons per optic nerve was 51 327 ± 3868 (mean ± standard error of the mean) in the lipopolysaccharide group and 54 569 ± 6687 (mean ± standard error of the mean) in the saline group. Optic nerve axon counts were not significantly different between lipopolysaccharide and saline groups (P = 0.67). CONCLUSIONS: Systemic lipopolysaccharide challenge had no discernible effect on optic nerve injury in laser-induced experimental glaucoma. These findings do not support the hypothesis that this model of experimental glaucoma involves inflammation and instead suggest that microglial activation may occur secondary to chronic neurodegeneration.

Investigations Into Bioenergetic Neuroprotection of Cone Photoreceptors: Relevance to Retinitis Pigmentosa.

Recent studies suggest cone degeneration in retinitis pigmentosa (RP) may result from intracellular energy depletion. We tested the hypothesis that cones die when depleted of energy by examining the effect of two bioenergetic, nutraceutical agents on cone survival. The study had three specific aims: firstly, we, studied the neuroprotective efficacies of glucose and creatine in an in vitro model of RP. Next, we utilized a well-characterized mouse model of RP to examine whether surviving cones, devoid of their inner segments, continue to express genes vital for glucose, and creatine utilization. Finally, we analyzed the neuroprotective properties of glucose and creatine on cone photoreceptors in a mouse model of RP. Two different bioenergy-based therapies were tested in rd1 mice: repeated local delivery of glucose and systemic creatine. Optomotor responses were tested and cone density was quantified on retinal wholemounts. The results showed that glucose supplementation increased survival of cones in culture subjected to mitochondrial stress or oxidative insult. Despite losing their inner segments, surviving cones in the rd1 retina continued to express the various glycolytic enzymes. Following a single subconjunctival injection, the mean vitreous glucose concentration was significantly elevated at 1 and 8 h, but not at 16 h after injection; however, daily subconjunctival injection of glucose neither enhanced spatial visual performance nor slowed cone cell degeneration in rd1 mice relative to isotonic saline. Creatine dose-dependently increased survival of cones in culture subjected to mitochondrial dysfunction, but not to oxidative stress. Despite the loss of their mitochondrial-rich inner segments, cone somas and axonal terminals in the rd1 retina were strongly positive for both the mitochondrial and cytosolic forms of creatine kinase at each time point examined. Creatine-fed rd1 mice displayed enhanced optomotor responses compared to mice fed normal chow. Moreover, cone density was significantly greater in creatine-treated mice compared to controls. The overall results of this study provide tentative support for the hypothesis that creatine supplementation may delay secondary degeneration of cones in individuals with RP.

Natural history of primary paediatric optic nerve sheath meningioma: case series and review.

PURPOSE: To study the natural history, clinical and radiological characteristics of primary paediatric optic nerve sheath meningioma (PPONSM). METHODS: Retrospective study of eight paediatric patients who were treated between 1994 and 2016 at the University Hospital Zurich, Switzerland and the Royal Adelaide Hospital, Australia. Clinical records and imaging studies were reviewed. RESULTS: The mean age at presentation was 11 years (range: 6-17 years). There were six female patients and two male patients. 2/8 patients had associated neurofibromatosis type 2. Patients were followed up for 71-297 months (mean 156±70 months). 6/8 patients were observed through the course of their disease and 2/8 patients were treated with radiotherapy. 2/8 patients who were observed had minimal change in vision and did not experience tumour growth after long-term follow-up. CONCLUSIONS: This is the largest PPONSM case series with long-term data on patients treated conservatively. We highlight that a small subset of these tumours are indolent and can be managed using observation alone.

A review of the mechanisms of cone degeneration in retinitis pigmentosa.

Retinitis pigmentosa (RP) is an inherited condition that features degeneration of rod and cone photoreceptors. In all forms of RP, the genetic mutation is expressed exclusively in rods; however, cones die too. The secondary death of cones in RP remains somewhat mysterious. A better understanding of the mechanisms that cause cone degeneration in RP could lead to novel treatments that preserve cones. There are a number of prevailing theories that attempt to explain cone degeneration in RP. One concept is that cone survival is dependent on trophic factors produced by rods. Another hypothesis is that cones suffer from a nutrient shortage after rods have been lost. Additionally, oxidative stress and pro-inflammatory microglial activation have also been suggested to play a role in cone death. The present review evaluates the evidence supporting these theories and provides an update on the mechanisms of cone degeneration in RP.