Comparative analysis of pathology and behavioural phenotypes in mouse models of Huntington's disease

The longitudinal characterisation of Huntington's disease (HD) mouse lines is essential for the understanding of the differential developmental time course, nature and severity of phenotype progression over time. This overview outlines detailed behavioural, neuropathological and gene expression studies in four HD mouse lines: R6/1, YAC128, HdhQ92 and HdhQ150 and outlines their relevance to human HD. The review describes the similarities and differences between the models at the behavioural, anatomical and genetic levels of pathology and how these phenotypes interact in the development of disease in the lines. The HdhQ150 mouse demonstrates the most similarities to the functional deficits observed in human HD. The neuropathological profile with early cortical development of intense aggregate/inclusion pathology in the YAC128 mouse suggests that this line most resembles the development of inclusion pathology in the human disease. The gene expression analyses of the mouse lines find significant similarities between each of the lines and human HD, which converge as the mice age. In the YAC128 and HdhQ92 mouse lines some severe functional deficits are progressive whilst others are not, despite the concomitant ongoing development of neuropathological and gene expression changes. We suggest that the YAC128 and R6/1 lines may be more representative of the juvenile form of HD. The suitability of the different mouse models studied here for different types of pre-clinical therapeutic trials is discussed.