Longitudinal analysis of the behavioural phenotype in R6/1 (C57BL/6J) Huntington's disease transgenic mice

Huntington's disease is caused by a single mutation on the HTT gene which produces an expansion in the number of glutamine repeats present in the huntingtin protein. This mutation results in an array of motor, cognitive and behavioural problems mediated by a progressive loss of striatal neurons and brain atrophy. The identification of behavioural phenotypes in mouse models of the disease provides a baseline of efficacy for therapeutic interventions. The R6/1 mouse line carries ∼115 CAG repeats and has an aggressive form of the disease. The aim of the present study was to undertake longitudinal behavioural characterisation of this mouse line in order to quantify the time course and severity of disease progression. In the present study, when compared to wildtype littermates, male R6/1 heterozygous mice demonstrated a progressive weight loss from 3 months of age. The R6/1 carriers also demonstrated a relatively stable motor coordination deficit on the rotarod, and progressive impairments on each aspect of the balance beam test: latency to orientate and traverse the beam; number of fore- and hind-limb footslips. The R6/1 carriers were less reactive to acoustic startle stimuli and displayed less inhibition to prepulse warning stimuli than their wildtype littermates. In the Morris water maze, the R6/1 carriers demonstrated a deficit on latency to find the platform and path length measures, which was apparent by 3 months of age but not further progressive. They also demonstrated fewer entries into the target zone during probe trials. The data from the present study demonstrate that the R6/1 mouse has a profound behavioural phenotype that includes motor and cognitive deficits, but that not all of these deficits were robustly progressive in nature.

► The authors sought to longitudinally characterise the nature, severity and development of behavioural abnormalities in the R6/1 (C57BL/6J) mouse model Huntington's disease.
► Male R6/1mice demonstrated a progressive loss of weight from 3 months of age.
► The R6/1 mice were slower to cross a balance beam and demonstrated a significantly greater number of hind- and fore-limb footslips than their wildtype littermates. These deficits were progressive in nature from around 3 months of age.
► The R6/1 mice were also impaired on the rotarod but their performance on this task was relatively stable over time.
► On the acoustic startle and prepulse inhibition test, the R6/1 were generally less reactive for the primary startle stimuli, and also demonstrated less prepulse inhibition of the primary startle.
► The R6/1 mice were also impaired on the Morris water test of spatial memory, demonstrating longer latencies and pathlengths to find the platform. However, these deficits were not progressive with age.
► We conclude that the R6/1 mouse on C57BL/6J background, exhibits a behavioural profile that demonstrates a progressive phenotype on some, but not all of the measures employed, and that these deficits are motoric and cognitive in nature.