Early Retinal Function Deficit without Prominent Morphological Changes in the R6/2 Mouse Model of Huntington’s Disease

Abstract

Huntington’s disease (HD) is an inherited neurodegenerative disorder that primarily affects the medium-size GABAergic neurons of striatum. The R6/2 mouse line is one of the most widely used animal models of HD. Previously the hallmarks of HD-related pathology have been detected in photoreceptors and interneurons of R6/2 mouse retina. Here we aimed to explore the survival of retinal ganglion cells (RGCs) and functional integrity of distinct retinal cell populations in R6/2 mice. The pattern electroretinography (PERG) signal was lost at the age of 8 weeks in R6/2 mice in contrast to the situation in wild-type (WT) littermates. This defect may be attributable to a major reduction in photopic ERG responses in R6/2 mice which was more evident in b- than a-wave amplitudes. At the age of 4 weeks R6/2 mice had predominantly the soluble form of mutant huntingtin protein (mHtt) in the RGC layer cells, whereas the aggregated form of mHtt was found in the majority of those cells from the 12-week-old R6/2 mice and onwards. Retinal astrocytes did not contain mHtt deposits. The total numbers of RGC layer cells, retinal astrocytes as well as optic nerve axons did not differ between 18-week-old R6/2 mice and their WT controls. Our data indicate that mHtt deposition does not cause RGC degeneration or retinal astrocyte loss in R6/2 mice even at a late stage of HD-related pathology. However, due to functional deficits in the rod- and cone-pathways, the R6/2 mice suffer progressive deficits in visual capabilities starting as early as 4 weeks; at 8 weeks there is severe impairment. This should be taken into account in any behavioral testing conducted in R6/2 mice.

Optical coherence tomography findings in Huntington’s disease: a potential biomarker of disease progression

“…However, The HD group has been analysed as a whole, and also separated into Manifest HD and pre-manifest HD groups. p values have been given for comparisons between the complete HD group and control participants * Denotes significance J Neurol drosophila and mouse models of HD, present with severe neuropathology, including progressive disorganisation of the photoreceptor layer and retinal dysfunction suggesting that the retina may exhibit the same neuronal pathology as the rest of the brain [39,[42][43][44][45]. In our study, inspection of OCT images did not reveal any obvious photoreceptor abnormalities.…”

Spectral-Domain Optical Coherence Tomography as a Potential Biomarker in Huntington's Disease

“…It is unclear whether the retina is affected in HD. Animal models using R6 mice suggested that there is an initial stage in which dysfunction of the photoreceptors, mainly cones, is observed, without any morphological changes (without evidence of significant cell loss) . This may be because of functional impairment of cone‐related proteins caused by huntingtin.…”

Visual Dysfunction in Huntington’s Disease: A Systematic Review

“…Although Knapp et al [18] report findings from a single case study, it is of note that reduced ERG amplitudes are in keeping with results from mouse models of Huntington's Disease [19]. Moreover, a key difference between the two studies is that whereas Knapp et al [18] report data from an unmedicated premanifest subject, Pearl et al [17] report data from a group of HD-manifest patients.…”