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The Journal of Neuroscience, August 22, 2007, 27(34):8989-8998; doi:10.1523/JNEUROSCI.1830-07.2007

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Neurobiology of Disease
Longitudinal Evaluation of the Hdh^(CAG)150 Knock-In Murine Model of Huntington's Disease

Mary Y. Heng,^1,2 Sara J. Tallaksen-Greene,² Peter J. Detloff,³ and Roger L. Albin^1,2,4

¹Neuroscience Graduate Program and ²Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109, ³Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama 36294, and ⁴Geriatrics Research, Education, and Clinical Center, Ann Arbor Veterans Administration Medical Center, Ann Arbor, Michigan 48105

Correspondence should be addressed to Dr. Roger L. Albin, 5023 Basic Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200. Email: ralbin{at}umich.edu

Several murine genetic models of Huntington's disease (HD) have been developed. Murine genetic models are crucial for identifying mechanisms of neurodegeneration in HD and for preclinical evaluation of possible therapies for HD. Longitudinal analysis of mutant phenotypes is necessary to validate models and to identify appropriate periods for analysis of early events in the pathogenesis of neurodegeneration. Here we report longitudinal characterization of the murine Hdh^(CAG)150 knock-in model of HD. A series of behavioral tests at five different time points (20, 40, 50, 70, and 100 weeks) demonstrates an age-dependent, late-onset behavioral phenotype with significant motor abnormalities at 70 and 100 weeks of age. Pathological analysis demonstrated loss of striatal dopamine D₁ and D₂ receptor binding sites at 70 and 100 weeks of age, and stereological analysis showed significant loss of striatal neuron number at 100 weeks. Late-onset behavioral abnormalities, decrease in striatal dopamine receptors, and diminished striatal neuron number observed in this mouse model recapitulate key features of HD. The Hdh^(CAG)150 knock-in mouse is a valid model to evaluate early events in the pathogenesis of neurodegeneration in HD.

Key words: Huntington disease; striatum; neurodegeneration; polyglutamine; trinucleotide repeat; mouse

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Received April 23, 2007; revised June 21, 2007; accepted June 21, 2007.

Correspondence should be addressed to Dr. Roger L. Albin, 5023 Basic Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200. Email: ralbin{at}umich.edu

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