Characterisation of retinal ganglion cell changes in the RCS rat, a retinal dystrophy model.
Doctoral thesis, UCL (University College London).
This study investigated retinal ganglion cell (RGC) changes in the Royal College of Surgeons (RCS) rat. The RCS rat represents a model of retinal dystrophies such as human retinitis pigmentosa. Retinal dystrophies have been attributed to defects in the retinal pigment epithelium and dysfunction and loss of photoreceptors. The process of photoreceptor degeneration has been well documented, however the natural history of changes in RGCs in this model is less well established. Apoptosis is one of the main pathways of cell death and has been investigated genetically and pharmacologically in many neuronal disorders. Apoptosis is an orchestrated form of cell "death by suicide" which is essential both in the development and normal maintenance of tissue function, but also involved in the pathogenesis of a number of severe neurodegenerative disorders such as Alzheimer’s, Parkinson's, and Huntington's disease. The detection of an early apoptotic, before DNA fragmentation occurs, has been proved difficult and is therefore not very well established. The Annexin V labelling technique used in this study allowed the demonstration of cells that are undergoing early apoptosis. The main aims of this study were to investigate RGC changes with age in the RCS rat using different techniques such as in vivo imaging, immunohistochemistry, histological Annexin V positive cell counts, ultrastructural assessment (TEM) of the retina and optic nerve and the functional assessment of the whole retina by electroretinographic recordings (ERGs). There was an-age-related increased intraocular pressure (IOP) with peak apoptosis at 6 months of age within the dystrophic RCS rats compared to the non-dystrophic control rats which had maintained IOPs throughout all age groups. Lowering the elevated IOPs did not affect RGC apoptosis counts, hence the IOP as a causative factor had to be excluded. In vivo images showed some nerve fiber thinning with age in the dystrophic animals and functional assessment revealed dysfuction of the ganglion cells within the dystrophic retinas beginning at 3 months of age. Retrograde Dil labeling, as well as immuhistochemistry confirmed apoptosing RGCs histologically and transmission electron microscopy ultrastructurally. Optic nerve axonal counts showed substantial RGC axon loss at 12 months of age within the dystrophic animals and a mild natural axonal loss with age within the non-dystrophic controls. The findings of this study suggest a much earlier time course of functional and morphological changes of the degenerating RGCs within the dystrophic RCS rat model than previously thought. The mechanism of death has still not been completely understood but this study contributes greatly towards the understanding as it identified apoptosis as the main pathway by which RGCs dye in the dystrophic RCS rat. This will be not only helpful in finding appropriate time points for therapeutical strategies such as electrical stimulation of cells or cell transplantations in RP and other retinal diseases but also help to develop appropriate monitoring methods for ocular diseases with apoptosing cells. An early diagnosis and appropriate follow up monitoring methods are essential for correct treatment therapies and might contribute to an increased success rate in rescuing vision loss.
|Title:||Characterisation of retinal ganglion cell changes in the RCS rat, a retinal dystrophy model|
|Additional information:||Authorisation for digitisation not received|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Wolfson Institute and Cancer Institute Administration > Cancer Institute > Research Department of Pathology|
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