title: 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.
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Kudwa
authors.forename: Liliana B
authors.initials: LB
authors.lastname: Menalled
authors.forename: Stephen
authors.initials: S
authors.lastname: Oakeshott
authors.forename: Carol
authors.initials: C
authors.lastname: Murphy
authors.forename: Richard
authors.initials: R
authors.lastname: Mushlin
authors.forename: John
authors.initials: J
authors.lastname: Fitzpatrick
authors.forename: Sam F
authors.initials: SF
authors.lastname: Miller
authors.forename: Kristi
authors.initials: K
authors.lastname: McConnell
authors.forename: Russell
authors.initials: R
authors.lastname: Port
authors.forename: Justin
authors.initials: J
authors.lastname: Torello
authors.forename: David
authors.initials: D
authors.lastname: Howland
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ramboz
authors.forename: Dani
authors.initials: D
authors.lastname: Brunner
references.citation: Mol Neurodegener. 2011 Aug 19;6:59
references.pmid: 21854568
references.citation: Neurobiol Dis. 2006 Feb;21(2):444-55
references.pmid: 16230019
references.citation: Chem Biol. 2011 Sep 23;18(9):1113-25
references.pmid: 21944750
references.citation: Hum Mol Genet. 2010 Apr 15;19(8):1528-38
references.pmid: 20097678
references.citation: Hum Mol Genet. 2003 Jul 1;12(13):1555-67
references.pmid: 12812983
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2911-6
references.pmid: 12589027
references.citation: J Neurosci. 2008 Jun 11;28(24):6182-95
references.pmid: 18550760
references.citation: Neurobiol Dis. 2008 Oct;32(1):1-9
references.pmid: 18638556
references.citation: Cell. 1993 Mar 26;72(6):971-83
references.pmid: 8458085
references.citation: Genes Brain Behav. 2003 Aug;2(4):214-9
references.pmid: 12953787
references.citation: Hum Mol Genet. 2006 May 1;15(9):1513-23
references.pmid: 16571604
references.citation: Hum Mol Genet. 1999 Mar;8(3):397-407
references.pmid: 9949199
references.citation: Brain Res Bull. 2012 Jun 1;88(2-3):121-9
references.pmid: 21624441
references.citation: Age (Dordr). 2012 Dec;34(6):1435-52
references.pmid: 21989972
references.citation: Neurobiol Aging. 1989 Nov-Dec;10(6):669-75
references.pmid: 2628778
references.citation: Neurobiol Dis. 2009 Sep;35(3):319-36
references.pmid: 19464370
references.citation: PLoS Curr. 2011 Apr 05;3:RRN1225
references.pmid: 21479110
references.citation: Front Syst Neurosci. 2011 Jul 15;5:61
references.pmid: 21811446
references.citation: J Gerontol. 1987 Jan;42(1):78-81
references.pmid: 3794202
references.citation: Behav Brain Res. 2010 Dec 25;214(2):193-200
references.pmid: 20493905
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11404-9
references.pmid: 10500189
references.citation: CNS Neurosci Ther. 2012 Jan;18(1):77-86
references.pmid: 21501423
references.citation: Neuron. 1999 May;23(1):181-92
references.pmid: 10402204
references.citation: Hum Mol Genet. 2005 Dec 15;14(24):3823-35
references.pmid: 16278236