title: Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington's disease transgenic mice.
abstract: Genetic murine models play an important role in the study of human neurological disorders by providing accurate and experimentally accessible systems to study pathogenesis and to test potential therapeutic treatments. One of the most widely employed models of Huntington's disease (HD) is the R6/2 transgenic mouse. To characterize this model further, we have performed behavioral and neuropathological analyses that provide a foundation for the use of R6/2 mice in preclinical therapeutic trials. Behavioral analyses of the R6/2 mouse reveal age-related impairments in dystonic movements, motor performance, grip strength, and body weight that progressively worsen until death. Significant neuropathological sequela, identified as increasing marked reductions in brain weight, are present from 30 days, whereas decreased brain volume is present from 60 days and decreased neostriatal volume and striatal neuron area, with a concomitant reduction in striatal neuron number, are present at 90 days of age. Huntingtin-positive aggregates are present at postnatal day 1 and increase in number and size with age. Our findings suggest that the R6/2 HD model exhibits a progressive HD-like behavioral and neuropathological phenotype that more closely corresponds to human HD than previously believed, providing further assurance that the R6/2 mouse is an appropriate model for testing potential therapies for HD.
authors.affiliation: Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, Massachusetts 01730, USA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.forename: James K
authors.initials: JK
authors.lastname: Kubilus
authors.forename: Karen
authors.initials: K
authors.lastname: Smith
authors.forename: Kerry
authors.initials: K
authors.lastname: Cormier
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Del Signore
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guelin
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hersch
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
mesh_terms: D000818:Animals; D001526:Behavioral Symptoms / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004421:Dystonia / Q000503:physiopathology; D005260:Female; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009043:Motor Activity / Q000502:physiology*; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016133:Polymerase Chain Reaction; D019680:Trinucleotide Repeat Expansion