Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation

Transgenic mice expressing exon 1 of the human Huntington's disease (HD) ge ne carrying a 141-157 CAG repeat (line R6/2) develop a progressive neurolog ical phenotype with motor symptoms resembling those seen in HD. We have cha racterized the motor deficits in R6/2 mice using a battery of behavioral te sts selected to measure motor aspects of swimming, fore- and hindlimb coord ination, balance, and sensorimotor gating [swimming tank, rotarod, raised b eam, fore- and hindpaw footprinting, and acoustic startle/prepulse inhibiti on (PPI)I. Behavioral testing was performed on female hemizygotic R6/2 tran sgenic mice (n = 9) and female wild-type littermates (n = 22) between 5 and 14 weeks of age. Transgenic mice did not show an overt behavioral phenotyp e until around 8 weeks of age. However, as early as 5-6 weeks of age they h ad significant difficulty swimming, traversing the narrowest square (5 mm) raised beam, and maintaining balance on the rotarod at rotation speeds of 3 3-44 rpm. Furthermore, they showed significant impairment in prepulse inhib ition tan impairment also seen in patients with HD). Between 8 and 15 weeks , R6/2 transgenic mice showed a progressive deterioration in performance on all of the motor tests. Thus R6/2 mice show measurable deficits in motor b ehavior that begin subtly and increase progressively until death. Our data support the use of R6/2 mice as a model of HD and indicate that they may be useful for evaluating therapeutic strategies for HD, particularly those ai med at reducing the severity of motor symptoms or slowing the course of the disease.