Behavioral abnormalities precede neuropathological markers in rats transgenic for Huntington's disease |
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| Authors: | Nguyen Huu Phuc Kobbe Philipp Rahne Henning Wörpel Till Jäger Burkard Stephan Michael Pabst Reinhard Holzmann Carsten Riess Olaf Korr Hubert Kántor Orsolya Petrasch-Parwez Elisabeth Wetzel Ronald Osmand Alexander von Hörsten Stephan |
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| Institution: | 1 Department of Functional and Applied Anatomy and
2 Department of Psychosomatics and Psychotherapy, Medical School of Hannover, Germany,
3 Department of Medical Genetics, University of Rostock, Germany,
4 Department of Medical Genetics, University of Tübingen, Germany,
5 Department of Anatomy and Cell Biology, RWTH Aachen University, Germany,
6 Department of Neuroanatomy and Molecular Brain Research, University of Bochum, Germany,
7 Department of Medicine, University of Tennessee, Knoxville, TN, USA and
8 Experimental Therapy, Franz-Penzoldt-Center, Friedrich-Alexander-University of Erlangen-Nürnberg, Germany |
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| Abstract: | Huntington's disease (HD) is caused by an expanded CAG repeatleading to the synthesis of an aberrant protein and to the formationof polyglutamine (polyQ)-containing inclusions and aggregates.Limited information is available concerning the associationof neuropathological markers with the development of behavioralmarkers in HD. Using a previously generated transgenic rat modelof HD (tgHD rat), we performed association studies on the time-courseof behavioral symptoms (motor function, learning, anxiety) andthe appearance of striatal atrophy, 1C2 immunopositive aggregatesand polyQ recruitment sites, a precursor to these aggregates.At the age of 1 month, tgHD rats exhibited reduced anxiety andimproved motor performance, while at 6 months motor impairmentsand at 9 months cognitive decline occurred. In contrast, polyQrecruitment sites appeared at around 6–9 months of age,indicating that HD-like behavioral markers preceded the appearanceof currently detectable neuropathological markers. Interestingly,numerous punctate sites containing polyQ aggregates were alsoseen in areas receiving afferents from the densely recruitingregions suggesting either transport of recruitment-competentaggregates to terminal projections where initially 1C2 positiveaggregates were formed or different internal properties of neuronsin different regions. Furthermore, striatal atrophy was observedat the age of 12 months. Taken together, our findings supportthe hypothesis of a dynamic process leading to region- and age-specificpolyQ recruitment and aggregation. The dissociation of onsetbetween behavioral and neuropathological markers is suggestiveof as yet undetected processes, which contribute to the earlyphenotype of these HD transgenic rats. |
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