Early behavioral deficits in R6/2 mice suitable for use in preclinical drug testing

Huntington's disease (HD) is a neurodegenerative disorder caused by an elongated glutamine repeat in huntingtin. Improved understanding of the molecular effects of the mutation opens new avenues for treatment. High-throughput automated behavioral tests that produce well-defined markers of disease progression are necessary for in vivo drug screening. We have identified early behavioral deficits in tests of motor function that are amenable to cost effective automated analysis in a mouse model of HD. Running wheel activity and climbing behavior were reduced in R6/2 HD transgenics from as early as 4.5 weeks of age, at a time when rotarod performance and grip strength were still normal. Power calculations showed that the running wheel test was appropriate for efficient, high-throughput drug screening at this early age. Furthermore, the data extend the range of behavioral deficits observed in 1-month-old R6/2 mice, an age when synaptic dysfunction can already be detected in the striatum.