Motor deficits associated with Huntington's disease occur in the absence of striatal degeneration in BACHD transgenic mice

摘要

Huntington's disease (HD) is an incurable neurodegenerative condition characterized by progressive motor and cognitive dysfunction, and depletion of neurons in the striatum. Recently, BACHD transgenic mice expressing the full-length human huntingtin gene have been generated, which recapitulate some of the motor and cognitive deficits seen in HD. In this study, we carried out a series of extensive behavioural and neuropathological tests on BACHD mice, to validate this mouse for preclinical research. Transgenic C57BL/6J BACHD and litter-matched wild-type mice were examined in a battery of motor and cognitive function tests at regular intervals up to 12 months of age. Brains from these mice were also analysed for signs of neurodegeneration and striatal and cortical volume sizes compared using anatomic 16.4T magnetic resonance imaging (MRI) brain scans. BACHD mice showed progressive motor impairments on rotarod and balance beam tests starting from 3 months of age, were hypoactive in the open field tests starting from 6 months of age, however, showed no alterations in gait and grip strength at any age. Surprisingly, despite these distinct motor deficits, no signs of neuronal loss, gliosis or blood-brain barrier degeneration were observed in the striatum of 12-month-old mice. MRI brain scans confirmed no reduction in striatal or cortical volumes at 12 months of age, and BACHD mice had a normal lifespan. These results demonstrate that classical Huntington's-like motor impairments seen in this transgenic model, do not occur due to degeneration of the striatum, and thus caution against the use of this model for preclinical studies into HD.