Selective Discrimination Learning Impairments in Mice Expressing the Human Huntington's Disease Mutation

Abstract

Cognitive decline is apparent in the early stages of Huntington's disease and progressively worsens throughout the course of the disease. Expression of the human Huntington's disease mutation in mice (R6/2 line) causes a progressive neurological phenotype with motor symptoms resembling those seen in Huntington's disease. Here we describe the cognitive performance of R6/2 mice using four different tests (Morris water maze, visual cliff avoidance, two-choice swim tank, and T-maze). Behavioral testing was performed on R6/2 transgenic mice and their wild-type littermates between 3 and 14.5 weeks of age, using separate groups of mice for each test. R6/2 mice did not show an overt motor phenotype until ∼8 weeks of age. However, between 3.5 and 8 weeks of age, R6/2 mice displayed progressive deterioration in specific aspects of learning in the Morris water maze, visual cliff, two-choice swim tank, and T-maze tasks. The age of onset and progression of the deficits in the individual tasks differed depending on the particular task demands. Thus, as seen in humans with Huntington's disease, R6/2 mice develop progressive learning impairments on cognitive tasks sensitive to frontostriatal and hippocampal function. We suggest that R6/2 mice provide not only a model for studying cognitive and motor changes in trinucleotide repeat disorders, but also a framework within which the functional efficacy of therapeutic strategies aimed at treating such diseases can be tested.

The power of automated high-resolution behavior analysis revealed by its application to mouse models of Huntington's and prion diseases

“…Most of the behavioral testing of HD mice is focused on their robust motor phenotypes (16), yet HD patients often present with psychological symptoms (7), and some cognitive defects have been described in HD Tgs (9,19). Our analysis of HC activity revealed substantial psychological abnormalities in HD Tgs, such as hypergrooming, decreased resting, and altered patterns of behavior with respect to the light-dark cycle.…”

“…We detected significant abnormalities in HD Tgs for most behaviors examined. Many behavioral abnormalities were observed at the reported age of disease onset for the HD Tgs, at 9-11 weeks (8)(9)(10)18). However, the sensitivity of high-resolution AMBA detected statistically significant differences as early as 6 weeks for five behaviors despite the limited sample size (n ϭ 7 WT and n ϭ 7 HD Tg; Fig.…”

“…Degeneration of the striatum and cortex leads to severe psychological and motor abnormalities, ending in death (7). The R6/2 mouse is the most widely used HD model, showing an early, severe disease phenotype, with declines in motor performance, cognitive abilities, and weight and premature death (8)(9)(10). PrDs have different etiologies and affect distinct regions of the brain.…”

Huntington disease skeletal muscle is hyperexcitable owing to chloride and potassium channel dysfunction

“…Patients with >40 CAG repeats develop the disease during middle age; those with >50 CAG repeats develop a more extreme juvenile form of the disease (1, 2). Because of the rapid onset of reduced activity at 4.5 wk of age (22,23) and overt motor defects at 8 wk of age (24)(25)(26), the R6/2 line most closely models the juvenile form of HD. The R6/2 line is often considered the model of choice for preclinical trials of potential HD therapeutics owing to its rapidly developing and welldescribed phenotype (1).…”

Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice

“…Although severe motor impairments characterize the disease, cognitive and memory deficits are also present and often appear in advance of other symptoms (3)(4)(5)(6). Impaired learning that occurs before or concurrent with motor dysfunction or neuron loss has been described for HD mouse models (7)(8)(9) as have deficits in hippocampal long-term potentiation (LTP) (10)(11)(12)(13), a form of synaptic plasticity widely regarded as a neurobiological substrate for memory. Understanding why LTP is severely impaired in HD mice could explain the cognitive dysfunction seen in patients with the disease.…”