Increased Body Weight of the BAC HD Transgenic Mouse Model of Huntington's Disease Accounts for Some but Not All of the Observed HD-like Motor Deficits

Abstract

The genome of the Bacterial Artificial Chromosome (BAC) transgenic mouse model of Huntington's Disease (BAC HD) contains the 170 kb human HTT locus modified by the addition of exon 1 with 97 mixed CAA-CAG repeats. BAC HD mice present robust behavioral deficits in both the open field and the accelerating rotarod tests, two standard behavioral assays of motor function. BAC HD mice, however, also typically present significantly increased body weights relative to wildtype littermate controls (WT) which potentially confounds the interpretation of any motor deficits associated directly with the effects of mutant huntingtin. In order to evaluate this possible confound of body weight, we directly compared the performance of BAC HD and WT female mice under food restricted versus free feeding conditions in both the open field and rotarod tasks to test the hypothesis that some of the motor deficits observed in this HTT-transgenic mouse line results solely from increased body weight. Our results suggest that the rotarod deficit exhibited by BAC HD mice is modulated by both body weight and non-body weight factors resulting from overexpression of full length mutant Htt. When body weights of WT and BAC HD transgenic mice were normalized using restricted feeding, the deficits exhibited by BAC HD mice on the rotarod task were less marked, but were still significant. Since the rotarod deficit between WT and BAC HD mice is attenuated when body weight is normalized by food restriction, utilization of this task in BAC HD mice during pre-clinical evaluation must be powered accordingly and results carefully considered as therapeutic benefit can result from decreased overall body weight and or motoric improvement that may not be related to body mass. Furthermore, after controlling for body weight differences, the hypoactive phenotype displayed by ad libitum fed BAC HD mice in the open field assay was not observed in the BAC HD mice undergoing food restriction. These findings suggest that assessment of spontaneous locomotor activity, as measured in the open field test, may not be the appropriate behavioral endpoint to evaluate the BAC HD mouse during preclinical evaluation since it appears that the apparent hypoactive phenotype in this model is driven primarily by body weight differences.

Body weight of female BAC HD and WT mice following either food restriction (FR) or free feeding at 65 (Panel A) and 95 (Panel B) weeks of age

Data are presented as mean ± S.E.M. * significant effect of genotype; # significant effect of food condition, p<0.05.

Performance of female BAC HD and WT mice in the rotarod task following either food restriction (FR) or free feeding at 66 (Panel A) and 96 (Panel B) weeks of age.

Data are presented as mean ± S.E.M. * significant effect of genotype; # significant effect of food condition, p<0.05.

Total locomotor activity (Panels A, B) and rearing rate in the center of the open field (Panels C, D) of female BAC HD and WT mice in the open field test under either food restricted (FR) or free feeding conditions at 66 (Panels A, C) and 95 (Panel B, D) weeks of age.

Data are presented as mean ± S.E.M. * significant effect of genotype; # significant effect of food condition, p<0.05.