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E. L. Fletcher, A. Hussain Batcha, U. Greferath, K. A. Vessey, J. Nithianantharajah, A. Hannan; Retinal Changes in the R6/1 Transgenic Mouse Model of Huntington’s Disease. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4049.
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Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion, resulting in an expanded polyglutamine tract in the huntingtin protein. While altered visual function has been reported in HD patients and mouse models, analysis at the level of the retina has not been thoroughly addressed. The aim of this study was to characterize in detail changes in retinal structure and function in the R6/1 transgenic mouse model of HD.
C57Bl6 (wildtype, WT) and R6/1 (HD) mice from 7 to 20 weeks of age were used in this study. Retinal function of WT (N=9) and HD mice (N=11) at 13-14 weeks of age was measured using a twin flash electroretinogram paradigm. Retinae from all age groups were aldehyde fixed and either resin embedded and Nissl stained, or sectioned at 12µm on a cryostat and processed for indirect immunofluorescence. Using antibodies targeted against specific cell types, and synaptic markers, changes in photoreceptors and inner retinal neurons were examined. Cell death was assessed by quantification of TUNEL positive cells.
Electrophysiological findings revealed significantly reduced cone and variable rod responses in HD mice compared with WT. HD mice showed a progressive decrease in cone opsin immunolabeling, but not peanut agglutinin lectin suggesting a defect in cone-opsin expression, rather than a loss of cone photoreceptors. A small number of photoreceptor nuclei displayed TUNEL labelling from 13 weeks of age and an increase in GFAP immunolabelling of Müller cell processes was detected suggesting the presence of retinal stress. Interestingly, from 13 weeks of age, there was evidence of ectopic synapses within the distal ONL that were immunoreactive for the ribbon markers RIBEYE, mGluR6 and PSD-95. Extension of rod and cone bipolar cells, towards ectopic synapses was also apparent.
These results suggest that with progression of the disease, HD mice display decreased cone opsin expression and cone dysfunction. This is accompanied by retinal stress and remodeling of bipolar cells. This data suggest that the retina is affected structurally as well as functionally in addition to neurodegeneration in Huntington’s disease.
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