title: Systematic behavioral evaluation of Huntington's disease transgenic and knock-in mouse models.
abstract: Huntington's disease (HD) is one of the few neurodegenerative diseases with a known genetic cause, knowledge that has enabled the creation of animal models using genetic manipulations that aim to recapitulate HD pathology. The study of behavioral and neuropathological phenotypes of these HD models, however, has been plagued by inconsistent results across laboratories stemming from the lack of standardized husbandry and testing conditions, in addition to the intrinsic differences between the models. We have compared different HD models using standardized conditions to identify the most robust phenotypic differences, best suited for preclinical therapeutic efficacy studies. With a battery of tests of sensory-motor function, such as the open field and prepulse inhibition tests, we replicate previous results showing a strong and progressive behavioral deficit in the R6/2 line with an average of 129 CAG repeats in a mixed CBA/J and C57BL/6J background. We present the first behavioral characterization of a new model, an R6/2 line with an average of 248 CAG repeats in a pure C57BL/6J background, which also showed a progressive and robust phenotype. The BACHD in a FVB/N background showed robust and progressive behavioral phenotype, while the YAC128 full-length model on either an FVB/N or a C57BL/6J background generally showed milder deficits. Finally, the Hdh(Q111) knock-in mouse on a CD1 background showed very mild deficits. This first extensive standardized cross-characterization of several HD animal models under standardized conditions highlights several behavioral outcomes, such as hypoactivity, amenable to standardized preclinical therapeutic drug screening.
authors.affiliation: PsychoGenics Inc., Tarrytown, NY 10591, USA.
authors.forename: Liliana
authors.initials: L
authors.lastname: Menalled
authors.forename: Bassem F
authors.initials: BF
authors.lastname: El-Khodor
authors.forename: Monica
authors.initials: M
authors.lastname: Patry
authors.forename: Mayte
authors.initials: M
authors.lastname: Suárez-Fariñas
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Orenstein
authors.forename: Benjamin
authors.initials: B
authors.lastname: Zahasky
authors.forename: Christina
authors.initials: C
authors.lastname: Leahy
authors.forename: Vanessa
authors.initials: V
authors.lastname: Wheeler
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
authors.forename: Marcy
authors.initials: M
authors.lastname: MacDonald
authors.forename: A Jennifer
authors.initials: AJ
authors.lastname: Morton
authors.forename: Gill
authors.initials: G
authors.lastname: Bates
authors.forename: Janet
authors.initials: J
authors.lastname: Leeds
authors.forename: Larry
authors.initials: L
authors.lastname: Park
authors.forename: David
authors.initials: D
authors.lastname: Howland
authors.forename: Ethan
authors.initials: E
authors.lastname: Signer
authors.forename: Allan
authors.initials: A
authors.lastname: Tobin
authors.forename: Daniela
authors.initials: D
authors.lastname: Brunner
mesh_terms: D000375:Aging; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D005838:Genotype; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009483:Neuropsychological Tests; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D012727:Sex Characteristics
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins