Behavioral abnormalities precede neuropathological markers in rats transgenic for Huntington's disease

Huu Phuc Nguyen, Philipp Kobbe, Henning Rahne, Till Wörpel, Burkard Jäger, Michael Stephan, Reinhard Pabst, Carsten Holzmann, Olaf Riess, Hubert Korr, Orsolya Kántor, Elisabeth Petrasch-Parwez, Ronald Wetzel, Alexander Osmand, Stephan von Hörsten

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93 Citations (Scopus)


Huntington's disease (HD) is caused by an expanded CAG repeat leading to the synthesis of an aberrant protein and to the formation of polyglutamine (polyQ)-containing inclusions and aggregates. Limited information is available concerning the association of neuropathological markers with the development of behavioral markers in HD. Using a previously generated transgenic rat model of HD (tgHD rat), we performed association studies on the time-course of behavioral symptoms (motor function, learning, anxiety) and the appearance of striatal atrophy, 1C2 immunopositive aggregates and polyQ recruitment sites, a precursor to these aggregates. At the age of 1 month, tgHD rats exhibited reduced anxiety and improved motor performance, while at 6 months motor impairments and at 9 months cognitive decline occurred. In contrast, polyQ recruitment sites appeared at around 6-9 months of age, indicating that HD-like behavioral markers preceded the appearance of currently detectable neuropathological markers. Interestingly, numerous punctate sites containing polyQ aggregates were also seen in areas receiving afferents from the densely recruiting regions suggesting either transport of recruitment-competent aggregates to terminal projections where initially 1C2 positive aggregates were formed or different internal properties of neurons in different regions. Furthermore, striatal atrophy was observed at the age of 12 months. Taken together, our findings support the hypothesis of a dynamic process leading to region- and age-specific polyQ recruitment and aggregation. The dissociation of onset between behavioral and neuropathological markers is suggestive of as yet undetected processes, which contribute to the early phenotype of these HD transgenic rats.

Original languageEnglish
Pages (from-to)3177-3194
Number of pages18
JournalHuman molecular genetics
Issue number21
Publication statusPublished - Nov 1 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Nguyen, H. P., Kobbe, P., Rahne, H., Wörpel, T., Jäger, B., Stephan, M., Pabst, R., Holzmann, C., Riess, O., Korr, H., Kántor, O., Petrasch-Parwez, E., Wetzel, R., Osmand, A., & von Hörsten, S. (2006). Behavioral abnormalities precede neuropathological markers in rats transgenic for Huntington's disease. Human molecular genetics, 15(21), 3177-3194.