Force-plate quantification of progressive behavioral deficits in the R6/2 mouse model of Huntington's disease.
The R6/2 mouse is a popular model of Huntington's disease (HD) because of its rapid progression and measurable behavioral phenotype. Yet current behavioral phenotyping methods are usually univariate (e.g., latency to fall from a rotarod) and labor intensive. We used a force-plate actometer and specialized computer algorithms to partition the data into topographically specific behavioral categories that were sensitive to HD-like abnormalities. Seven R6/2 male mice and 7 wild-type (WT) controls were placed in a 42 cm x 42 cm force-plate actometer for 20-min recording sessions at 6-7, 8-9, 10-11 and 12-13 weeks of age. Distance traveled, number of wall rears, and number of straight runs (traveling 175 mm or more in 1.5s) were reduced in R6/2 relative to WT mice at all ages tested. Low mobility bouts (each defined as remaining continuously in a virtual circle of 15 mm radius for 5s) were increased in R6/2 mice at 6-7 weeks and beyond. Independent of body weight, force off-load during wall rears was reduced in R6/2 mice except at 6-7 weeks. Power spectra of force variation during straight runs indicated an age-related progressive loss of rhythmicity in R6/2 compared to WT, suggesting gait dysrhythmia and dysmetria. Collectively, these data, which extend results obtained with other widely different behavioral phenotyping methods, document a multifaceted syndrome of motor abnormalities in R6/2 mice. We suggest, moreover, that the force-plate actometer offers a high-throughput tool for screening drugs that may affect symptom expression in R6/2 or other HD model mice.
Fowler
Stephen C
SC
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, USA. scfowler@ku.edu
Miller
Benjamin R
BR
Gaither
Thomas W
TW
Johnson
Michael A
MA
Rebec
George V
GV
D000367:Age Factors; D000465:Algorithms; D000818:Animals; D001835:Body Weight; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D005583:Fourier Analysis; D005838:Genotype; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000150:complications / Q000175:diagnosis / Q000523:psychology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009069:Movement Disorders / Q000175:diagnosis / Q000209:etiology / Q000523:psychology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009483:Neuropsychological Tests; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D019680:Trinucleotide Repeat Expansion
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins