Light and electron microscopic characterization of the evolution of cellular pathology in the R6/1 Huntington's disease transgenic mice

Bayram-Weston, Zubeyde, Jones, Lesley ORCID: https://orcid.org/0000-0002-3007-4612, Dunnett, Stephen Bruce ORCID: https://orcid.org/0000-0003-1826-1578 and Brooks, Simon Philip ORCID: https://orcid.org/0000-0001-9853-6177 2012. Light and electron microscopic characterization of the evolution of cellular pathology in the R6/1 Huntington's disease transgenic mice. Brain Research Bulletin 88 (2-3) , pp. 104-112. 10.1016/j.brainresbull.2011.07.009

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Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion of CAG repeats in the Htt gene. Examination of the post-mortem brains of HD patients shows the presence of diffuse nuclear htt immunoreactivity and intra-nuclear inclusions. The aim of this study was to produce a detailed characterization of the neuronal pathology in the R6/1 transgenic mouse model. The R6/1 carrier mice demonstrate intra-nuclear and extra-nuclear inclusions with the S830 htt antibody at 2–11 months of age. The distribution pattern of neuronal intra-nuclear inclusions (NIIs) was irregular in several brain regions including the striatum, cortex and hippocampus. A greater number of NIIs were found in the ventral striatum than in the dorsal striatum. In the globus pallidus, cerebellum and thalamus the pattern of inclusion formation was relatively consistent over time. At 4 and 6 months of age, the R6/1 mice showed increased glial fibrillary acid protein (GFAP) immunoreactivity in the cortex compared to their wildtype littermates, yet no difference was found in the striatum. Analysis by electron microscopy found that neurons from the R6/1 carriers contained a densely packed cytoplasm at 1.5 months of age, with some neurons displaying structural abnormalities including vacuolization and nuclear membrane folding. No NIIs were detected at this age, but by 7 months of age, NIIs were present with severe cellular vacuolization. The present study indicates that a decrease in striatal volume with cell loss is present in young (2 months) R6/1 mice, and the distribution of NIIs is robust and widespread, with considerably temporal and spatial variation in NII development between mice.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords:	Huntington's disease; Aggregations; Inclusions; R6/1; Transgenic mice; Transmission electron microscope (TEM)
Additional Information:	Behavioural, Anatomical, and Genetic Characterisation of Mouse and Rat Models of Huntington’s Disease
Publisher:	Elsevier
ISSN:	0361-9230
Last Modified:	11 Mar 2023 02:34
URI:	https://orca.cardiff.ac.uk/id/eprint/41717

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