R6/2 transgenic Mouse Model
Huntington’s disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable at middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea. The disease is caused by an autosomal dominant mutation of the huntingtin gene.
The mutation of the huntingtin gene codes for a different form of the huntingtin protein, whose presence results in gradual damage of specific areas of the brain. Symptoms of the disease can vary between individuals and among affected members of the same family, but progress predictable for most individuals. The earliest symptoms are a general lack of coordination and an unsteady gait.
As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioral and psychiatric problems. Physical abilities are gradually impeded until coordinated movement becomes very difficult. Mental abilities generally decline into dementia.
R6/2 mice model human Huntington’s disease (HD) by expressing a portion of the human HD gene under human gene promoter elements (1 kb of 5 UTR sequence and exon 1 together with ~140 CAG repeats). Expression of this amino-terminal fragment of the huntingtin protein with its polyglutamine expansion is sufficient to reproduce the phenotype of human HD.
Figure. (A) Rota Rod performance of R6/2 mice: motor coordination expressed as time until falling off the rod over age (tg: n=10; ntg: n=19); two-way ANOVA with Bonferroni`s posttest. **p<0.01; ***p<0.001.
(B) Two Choice Swim Test: percentage of wrong choices during 5 training days (5 trials per day) followed by one reversal day (15 trials, n=14 per group); two-way ANOVA with Bonferroni`s posttest. ***p<0.001.
Figure. (C, D) Contextual Fear Conditioning Test of R6/2 mice: freezing performance during the contextual and cued phase of the CFC (n=14 per group); unpaired t-test. *p<0.05; **p<0.01.
Figure. (E, F) Quantitative and qualitative comparison of astrocytosis: R6/2 mice feature increased emergence of astrocytes compared to the nTg control. (E): Graphs represent the number of astrocytes per mm². *p<0.05; **p<0.01. (F): Dapi (blue) plus GFAP (red) exemplarily in the primary somatosensory cortex and CA1 region of the hippocampus.
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Rebecca J. Carter, Lisa A. Lione, Trevor Humby, Laura Mangiarini, Amarbirpal Mahal, Gillian P. Bates, Stephen B. Dunnett and A. Jennifer Morton. The Journal of Neuroscience, April 15, 1999,19(8):3248–3257. Characterization of Progressive Motor Deficits in Mice Transgenic for the Human Huntington’s Disease Mutation
Lisa A. Lione, Rebecca J. Carter, Mark J. Hunt, Gillian P. Bates, A. Jennifer Morton and Stephen B. Dunnett. The Journal of Neuroscience, December1, 1999,19(23):10428–10437. Selective Discrimination Learning Impairments in Mice Expressing the Human Huntington’s Disease Mutation
Laura Mangiarini, Kirupa Sathasivam, Mary Seller, Barbara Cozens, Alex Harper, Colin Hetherington, Martin Lawton, Yvon Trottier, Hans Lehrach, Stephen W. Davies and Gillian P. Bates. Cell, Vol. 87, 493–506, November 1, 1996. Exon1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice