Abstract
A variety of mouse models have been developed that express mutant huntingtin (mHTT) leading to aggregates and inclusions that model the molecular pathology observed in Huntington’s disease. Here we show that although homozygous HdhQ150 knock-in mice developed motor impairments (rotarod, locomotor activity, grip strength) by 36 weeks of age, cognitive dysfunction (swimming T maze, fear conditioning, odor discrimination, social interaction) was not evident by 94 weeks. Concomitant to behavioral assessments, T2-weighted MRI volume measurements indicated a slower striatal growth with a significant difference between wild type (WT) and HdhQ150 mice being present even at 15 weeks. Indeed, MRI indicated significant volumetric changes prior to the emergence of the “clinical horizon” of motor impairments at 36 weeks of age. A striatal decrease of 27% was observed over 94 weeks with cortex (12%) and hippocampus (21%) also indicating significant atrophy. A hypothesis-free analysis using tensor-based morphometry highlighted further regions undergoing atrophy by contrasting brain growth and regional neurodegeneration. Histology revealed the widespread presence of mHTT aggregates and cellular inclusions. However, there was little evidence of correlations between these outcome measures, potentially indicating that other factors are important in the causal cascade linking the molecular pathology to the emergence of behavioral impairments. In conclusion, the HdhQ150 mouse model replicates many aspects of the human condition, including an extended pre-manifest period prior to the emergence of motor impairments.
Highlights
The cause of Huntington’s disease (HD) has been identified as the abnormal expansion of a CAG repeat in exon 1 of the huntingtin gene (HTT), that is transmitted in an autosomal dominant fashion [1]
To provide a link between molecular pathology with behavioral performance, as well as structural brain changes, a correlational analysis in the same cohort of animals is required, as we have previously described for the N-terminal fragment models R6/2 [30] and R6/1 [31]
Wild type (WT) and HdhQ150 mice of both genders were included in a longitudinal study that repeatedly evaluated behavioral and tissue changes from 9 until 94 weeks of age when animals were perfusion fixed for post-mortem histopathological evaluations (Fig 1A)
Summary
The cause of Huntington’s disease (HD) has been identified as the abnormal expansion of a CAG repeat in exon 1 of the huntingtin gene (HTT), that is transmitted in an autosomal dominant fashion [1]. This CAG expansion encodes a polyglutamine tract in the huntingtin protein (HTT), that is prone to aggregate and eventually manifests in neurodegeneration [2]. Pre-manifestation markers of the condition (i.e. biological changes that occur prior to symptom-based diagnosis) have been identified as subtle brain changes on magnetic resonance images (MRI) that are predictive of disease burden [5,6,7,8]. Rodent models of HD provide an excellent experimental system to thoroughly investigate these MRI-based biomarkers and associate these with cytoarchitectural and molecular changes in a controlled fashion [9]
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