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Human Molecular Genetics Advance Access first published online on May 23, 2008
This version published online on May 28, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn159
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Sex differences in a transgenic rat model of Huntington's disease: decreased 17ß-estradiol levels correlate with reduced numbers of DARPP32+ neurons in males

Felix J. Bode1,#, Michael Stephan1,#, Hendrik Suhling1, Reinhard Pabst1, Rainer H. Straub2, Kerstin A. Raber3, Michael Bonin4, Huu Phuc Nguyen4, Olaf Riess4, Andreas Bauer5,6, Charlotte Sjoberg7, Åsa Petersén7 and Stephan von Hörsten1,3,*

1 Institute of Functional and Applied Anatomy, Medical School of Hannover, 30625 Hannover, Germany 2 Department of Internal Medicine I, University Regensburg, 93042 Regensburg, Germany 3 Experimental Therapy, Franz-Penzoldt-Center, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany 4 Department of Medical Genetics, University of Tübingen, 72076 Tübingen, Germany 5 Institute of Neurosciences and Biophysics, Research Centre Juelich, 52425 Juelich, Germany 6 Department of Neurology, Heinrich-Heine University Duesseldorf, 40001 Duesseldorf, Germany 7 Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden

* Correspondence: Dr. Stephan von Hörsten, Experimental Therapy, Franz-Penzoldt-Center, Friedrich-Alexander-University Erlangen-Nürnberg, Palmsanlage 5, 91054 Erlangen, Germany; email: Stephan.v.Hoersten{at}ze.uni-erlangen.de; phone: (49) 9131 85 23504; fax: (49) 9131 85 23502

Received March 10, 2008; Revised May 8, 2008; Accepted May 21, 2008

Recent clinical studies have highlighted that female sex hormones represent potential neuroprotective mediators against damage caused by acute and chronic brain diseases. This evidence has been confirmed by experimental studies documenting the protective role of female sex hormones both in vitro and in vivo, although these studies did not specifically focus on Huntingtons disease (HD). We therefore investigated the onset and course of HD in female and male transgenic (tg) HD (CAGn51) and control rats across age and focused on three aspects: (i) behavioral and physiological alterations (energy expenditure, home-cage activity, emotional disturbance, and motor dysfunction), (ii) morphological markers (numbers and characteristics of striatal DARPP32+ medium-sized spiny neurons (MSNs) and dopamine receptor autoradiography), and (iii) peripheral sex hormone levels as well as striatal estrogen receptor expression. Independent of their sex, tgHD rats exhibited increased levels of food intake, elevated home-cage activity scores, and anxiolytic-like behavior, while only males showed an impairment of motor function. In line with the latter finding, loss and atrophy of DARPP32+ MSNs were apparent only in male tgHD rats. This result was associated with a decreased striatal dopamine D1 receptor density and lower plasma levels of 17β-estradiol at the age of 14 months. Since DARPP32+ MSNs expressed both {alpha}- and ß-estrogen receptors and showed a correlation between cell numbers and 17ß-estradiol levels, our findings suggest sex-related differences in the HD phenotype pointing to a substantial neuroprotective effect of sex hormones and opening new perspectives on the therapy of HD.

# both authors contributed equally as first authors


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