Longitudinal Behavioral Cross-sectional Transcriptional and Histopathological Characterization of a Knock-in Mouse Model of Huntingtons Disease with 140 CAG Repeats

摘要

The discovery of the gene mutation responsible for Huntington's Disease (HD), huntingtin, in 1993 allowed for a better understanding of the pathology of the and enabled development of animal models. HD is caused by the expansion of a polyglutamine repeat region in the N-terminal of the huntingtin protein. Here we examine the behavioral, transcriptional, histopathological and anatomical characteristics of a knock-in HD mouse model with a 140 polyglutamine expansion in the huntingtin protein. This CAG 140 model contains a portion of the human exon 1 with 140 CAG repeats knocked into the mouse huntingtin gene. We have longitudinally examined the rearing behavior, accelerating rotarod, constant speed rotarod and gait for the heterozygote, homozygote and their non-transgenic littermates and have found a significant difference in the afflicted mice. However, while there were significant differences between the non-transgenic and the knock-in mice, these behaviors were not progressive. As in HD, we show that the CAG 140 mice also have a significant decrease in striatally enriched mRNA transcripts. In addition, striatal neuronal intranuclear inclusion density increases with age. Lastly these CAG 140 mice show slight cortical thinning compared to unaffected littermates, similarly to the cortical thinning recently reported in HD.