Abstract
Huntington’s disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6/2 mouse model of HD expresses a mutant version of exon 1 HTT and develops motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Despite the vast number of studies that have been performed on this model, the association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood. In an attempt to link these factors, we have performed longitudinal assessments of behavior (rotarod, open field, passive avoidance) and of regional brain abnormalities determined through magnetic resonance imaging (MRI) (whole brain, striatum, cortex, hippocampus, corpus callosum), as well as an end-stage histological assessment. Detailed correlative analyses of these three measures were then performed. We found a gender-dependent emergence of motor impairments that was associated with an age-related loss of regional brain volumes. MRI measurements further indicated that there was no striatal atrophy, but rather a lack of striatal growth beyond 8 weeks of age. T2 relaxivity further indicated tissue-level changes within brain regions. Despite these dramatic motor and neuroanatomical abnormalities, R6/2 mice did not exhibit neuronal loss in the striatum or motor cortex, although there was a significant increase in neuronal density due to tissue atrophy. The deposition of the mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the brain. End-stage histopathological assessments were not found to be as robustly correlated with the longitudinal measures of brain atrophy or motor impairments. In conclusion, modeling pre-manifest and early progression of the disease in more slowly progressing animal models will be key to establishing which changes are causally related.
Highlights
Huntington’s disease (HD) is a devastating autosomal dominant disorder, caused by a CAG/polyglutamine repeat expansion (HDCRG, 1993)
We describe how a longitudinal assessment of behavioral performance and regional brain changes, as well as molecular and cellular pathological markers can inform on how these distinct measures are associated with each other
The principal findings were that (1) R6/2 developed progressive behavioral impairments that were influenced by gender and associated with changes in brain structures as measured by longitudinal magnetic resonance imaging (MRI); (2) despite dramatic brain shrinkage and widespread deposition of mutant huntingtin (mHTT), there was no neuronal loss in the regions investigated; (3) MRI detected regional brain abnormalities were associated with molecular and cellular pathology, as well as behavioral deficits
Summary
Huntington’s disease (HD) is a devastating autosomal dominant disorder, caused by a CAG/polyglutamine repeat expansion (HDCRG, 1993). The variability in disease symptoms and progression, as well as the unavailability of affected tissue during the early stage of disease, impede efforts to link molecular pathology to both brain atrophy and behavioral dysfunction. To overcome these issues and improve our understanding of disease progression, rodent models of HD have been developed. We have subsequently shown that this is generated through the mis-splicing exon 1, indicating that the R6/2 mice are a model for the aberrant splicing that occurs in HD (unpublished) This current study is part of a continuing detailed comparison of the progressive pathologies exhibited by the R6 and knock-in mouse models
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