Photoreceptor degeneration in retinitis pigmentosa

Project Aim

The aim of this project was to map the anatomical and neurochemical architecture in the retinas of mice models so we can better understand the changes which occur in the presence of retinal degeneration, with a focus on the time period upon which these changes occurred. Further to this, we investigated the impact of excessive light exposure in exacerbating the rate of cell death, and how pharmacological intervention may slow the progression of cell loss in degenerative retinal disease.

Project Summary

Firstly, we mapped the anatomical and neurochemical architecture of both normal and animal models with retinal degeneration. In this case the study was conducted on mice models with retinitis pigmentosa (P23H rats). In normal developing mice, we Identified the age at which the cells of the retina begin to communicate with each other through neurotransmitters. This was the basis of further investigations which looked at the structural and neurochemical changes that occur in the presence of degenerative retinal disease. It was found that in mice with retinal degeneration, remodelling of the anatomical structure and neurochemical pathways occurs. This means that in cases of advanced retinal degeneration, intervention through methods such as transplantation or implantation become difficult.
Although the structural changes that occur in retinal degeneration have been understood for some time, this study was the first to map the neurochemical changes. In other words, this study identified the changes that occur to the way cells communicate with each other in the presence of degenerative retinal disease. This was done by identifying unique neurotransmitter receptors (communication molecules) in different subpopulations of retinal cells. If the appropriate receptors are not expressed it would become impossible for cells in the retina to communicate, particularly in the context of potential intervention measures such as transplantation and gene therapy. Furthermore, It was identified that in animal models with retinal degeneration there was early loss of unique cell types in the retina and changes to neurochemical receptor expression.
Following on from this, a ‘critical period’ was discovered where intervention for degenerative retinal disease may be possible (a period of time when cell receptor expression may still be modifiable). Beyond this critical period, such as in advanced retinal degeneration, changes in structure and cell communication may render the retinal receptor expression difficult to modify.
One way In which retinal degeneration can be accelerated is with excessive light exposure. We investigated this mechanism both in normal and animal models with retinal degeneration with the focus of characterising the process of cell death. We found that photoreceptor death occurs through two mechanisms. The first involves unregulated ion flow (excessive flow of ions into the photoreceptors of the retina). The second was by apoptosis (programmed cell death). This suggests that therapeutic strategies directed towards preventing cell death in the retina need to be focussed towards controlling both the ion flow and apoptosis pathways. Using this, we attempted to pharmacologically slow the progress of retinal degeneration. The results from this are still in the process of being analysed.

This project was able to successfully map out both the anatomical and neurochemical changes that occur throughout retinal degeneration in mouse models. Through this, we Identified the ‘critical period’ in which intervention may be possible. Furthermore, we showed how progression of retinal degeneration may be modified by excessive light exposure (which accelerated death of the photoreceptors) and by pharmacological intervention (which may slow the rate of photoreceptor death).

Peer reviewed articles

Yu Ty, Acosta ML, Ready S, Cheong YL, Kalloniatis M, 2007. Light exposure causes functional changes in the retina: increased photoreceptors cation channel permeability, photoreceptor apoptosis and altered retinal metabolic function. Journal of Neurochemistry. 103: 714-724.

Acosta ML, Chua J, Kalloniatis M, 2007. Functional activation of glutamate ionotropic receptors in the developing mouse retina. Journal of Comparative Neurology. 500(5) : 923-941.

Chua J, Fletcher EL, Kalloniatis M, 2009. Functional remodeling of glutamate receptors by inner retinal neurons occurs from an early stage of retinal degeneration. Journal of Comparative Neurology. 514 (5), 473-491.

Download the Researcher's Final Report