Longitudinal analysis of the behavioural phenotype in Hdh(CAG)150 Huntington's disease knock-in mice.
In people with Huntington's disease, an expanded CAG repeat sequence on the HTT gene confers a toxic gain function resulting in a progressive and fatal neurodegeneration. The Hdh((CAG)Q150) Huntington's disease mouse line is a knock-in model of the disease that carries ∼150 CAG repeats on the normal mouse Htt locus. To determine that these mice are a useful model of the disease, they were assessed longitudinally for motor and cognitive deficits relevant to the human disease state. Each test was conducted bi-monthly across the lifespan of the animal. The results indicate that the Hdh(Q150/Q150) mice were impaired on each of the measures used, with deficits appearing on a 3-stage water maze test at 4 months of age and on prepulse inhibition at 6 months of age, both of which were prior to the manifestation of motor abnormalities. Grip strength, as measured by the inverted cage lid test, was reduced in the Hdh(Q150/Q150) mice from 10 months of age, when the male mice also exhibited weight loss relative to their wildtype littermates. On the accelerating rotarod, deficits in the carrier mice did not appear until they were 21 months old. Our results demonstrate that the Hdh((CAG)150) is a valid model of HD that displays early and progressive cognitive deficits that precede the onset of motor abnormalities.
Brooks
Simon
S
Brain Repair Group, School of Biosciences, Cardiff University, Wales, UK. brookssp@cardiff.ac.uk
Higgs
Gemma
G
Jones
Lesley
L
Dunnett
Stephen B
SB
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008137:Longitudinal Studies; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins