EURON and THEME joint PhD meeting

61
EURON and THEME joint meeting 2011
Hyperdopaminergic status in Huntington’s disease
Ali Jahanshahi 1,2,3 , Rinske Vlamings 1,2,3 , Dagmar Zeef 1,2,3 , Harry Steinbusch 1,3 and
Yasin Temel 1,2,3
Departments of 1 Neuroscience and 2 Neurosurgery, Maastricht University Medical Centre, Maastricht,
The Netherlands; 3 European Graduate School of Neuroscience (EURON).
Introduction
Huntington’s disease (HD) is a neurodegenerative disorder characterized by
progressive cognitive impairments and chorea. The latter has been linked to
an increased dopaminergic neurotransmission in the striatum. Treatment with
dopamine (DA) antagonist or DA depleting drugs can reduce chorea. However,
the origin of this hyperdopaminergic status remains unknown. Tracing studies
have shown that dopaminergic input to the striatum comes from the substantia
nigra pars compacta (SNc), ventral tegmental area (VTA), and a specific cell
population of the dorsal raphe nucleus (DRN). We tested the hypothesis that
elevated striatal DA levels are caused by changes in the number of dopaminergic
neurons in the SNc, VTA and DRN in a transgenic rat model of HD (tgHD) and in
the DRN of human HD specimens.
Materials and methods
Rodents were transgenic HD (tgHD) rats (homozygous, hemiozygous HD
and wildtype littermates). Brains were cut serially and processed for
immunohistochemical staining. Sections containing the striatum, VTA, SNc, and
DRN were immunohistochemically processed for tyrosine hydroxylase (TH), the
rate-limiting enzyme in the synthesis of DA. In addition, we processed another
series of brain sections containing the DRN for phenylalanine hydroxylase (PH8)
immunohistochemistry, rate limiting enzyme in serotonin production. The number
of TH-ir and PH8-ir cells in tgHD rats was evaluated using Stereology and the level
of TH expression in the striatum were assessed by optical densitometry.
Human brain sections of HD patients and controls containing the DRN were
stained for TH and PH8. The number TH and PH8 containing cells in the DRN
were evaluated semi-quantitatively.
Results
The number of TH-ir cells in the tgHD rats was significantly higher as compared
to the WT littermates, in all investigated regions in tgHD rats. Measurements of
the optical densities showed that the TH-ir in the dorsal and ventral striatum
was significantly higher in the tgHD rats as compared to the WT counterparts.