Profiles of motor and cognitive impairment in the transgenic rat model of Huntington's disease

The transgenic Huntington's disease (tgHD) rat strain provides a well regarded transgenic animal model of Huntington's disease, offering the prospect for a more detailed functional analysis in rats, along with neurological and therapeutic interventions, than is possible in the more widely available mouse models. In the present experiments, we compare the performance of heterozygous and homozygous tgHD rats against wildtype littermates on a range of motor and cognitive assessments in five separate cohorts of rats between 8 and 22 months of age. Male but not female heterozygous tgHD rats exhibit modest motor deficits in rotarod and staircase reaching tests, whereas most cognitive tests (including object recognition, exploration of novelty, delayed alternation, choice reaction time, and serial implicit learning tasks) revealed at best small or inconsistent deficits, in homozygous as well as heterozygous animals, up to 22 months of age. Thus, although we have observed modest but clear-cut deficits in motor phenotype, with a sex difference in line with previous reports, we have not established a robust cognitive impairment in this strain on a range of tasks sensitive to frontostriatal function, as required for testing novel (symptomatic, protective or reparative) therapeutics in a robust, valid, animal model of human Huntington's disease.

► Transgenic rats carrying a mutant fragment of the human HTT gene model the neuropathology of Huntington's disease.
► We evaluate motor and cognitive changes in the first (tgHD) transgenic rat model of Huntington's disease.
► We replicate previous reports of sex differences in motor tests (more impaired in males).
► We do not find stable or robust deficits in a range of ‘frontostriatal’ cognitive tests.
► This model does not (yet) offer a reliable framework to assess novel therapeutics.