title: Sex differences in a transgenic rat model of Huntington's disease: decreased 17beta-estradiol levels correlate with reduced numbers of DARPP32+ neurons in males.
abstract: 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 Huntington's disease (HD). We therefore investigated the onset and course of HD in female and male transgenic (tg) HD (CAG(n51)) 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, whereas 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 17beta-estradiol at the age of 14 months. As DARPP32(+) MSNs expressed both alpha- and beta-estrogen receptors and showed a correlation between cell numbers and 17beta-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.
authors.affiliation: Institute of Functional and Applied Anatomy, Medical School of Hannover, 30625 Hannover, Germany.
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Bode
authors.forename: Michael
authors.initials: M
authors.lastname: Stephan
authors.forename: Hendrik
authors.initials: H
authors.lastname: Suhling
authors.forename: Reinhard
authors.initials: R
authors.lastname: Pabst
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Straub
authors.forename: Kerstin A
authors.initials: KA
authors.lastname: Raber
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.forename: Huu Phuc
authors.initials: HP
authors.lastname: Nguyen
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Andreas
authors.initials: A
authors.lastname: Bauer
authors.forename: Charlotte
authors.initials: C
authors.lastname: Sjoberg
authors.forename: Asa
authors.initials: A
authors.lastname: Petersén
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000473:pathology / Q000503:physiopathology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D004958:Estradiol / Q000097:blood*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D006816:Huntington Disease / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009043:Motor Activity; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497930:Ppp1r1b protein, rat; D004958:Estradiol; D005680:gamma-Aminobutyric Acid