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Brain Res. 2019 Jan 31. pii: S0006-8993(19)30066-6. doi: 10.1016/j.brainres.2019.01.041. [Epub ahead of print]

Altered expression of dopaminergic cell fate regulating genes prior to manifestation of symptoms in a transgenic rat model of Huntington's disease.

Author information

1
Departament de Biologia, Universitat de Girona, Girona, Spain. Electronic address: gemma.huguet@udg.edu.
2
Department of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands. Electronic address: y.temel@maastrichtuniversity.nl.
3
Departament de Biologia, Universitat de Girona, Girona, Spain. Electronic address: elisabet.kadar@udg.edu.
4
Department of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands. Electronic address: sylvana.pol@maastrichtuniversity.nl.
5
Department of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands. Electronic address: j.casacacarreira@maastrichtuniversity.nl.
6
Departament de Psicobiologia i de Metodologia de les Ciències de la Salut, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain. Electronic address: pilar.segura@uab.cat.
7
Department of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands. Electronic address: a.jahanshahi@maastrichtuniversity.nl.

Abstract

Hyperactivity of the dopaminergic pathway is thought to contribute to clinical symptoms in the early stages of Huntington's disease (HD). It is suggested to be result of a reduced dopaminergic inhibition by degeneration of medium spiny neurons in the striatum. Previously, we have shown that the number of dopaminergic cells is increased in the dorsal raphe nucleus (DRN) of HD patients and transgenic HD (tgHD) rats during the manifestation phase of the disease; as well as in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) of tgHD rats. To address whether these changes are secondary to neurodegeneration or take place in the pre-manifest phase of the disease, we examined the expression of genes controlling neuronal cell fate and genes that define dopaminergic cell phenotype. In the SNc-VTA of tgHD rats, Msx1 was upregulated, which correlated with an altered expression of transcription factors Zbtb16 and Tcf12. Zbtb16 was upregulated in the DRN and it was the only gene that showed a correlated expression in the tgHD rats between SNc-VTA and DRN. Zbtb16 may be a candidate for regionally tuning its cell populations, resulting in the increase in dopaminergic cells observed in our previous studies. Here, we demonstrated an altered expression of genes related to dopaminergic cell fate regulation in the brainstem of 6 months-old tgHD rats. This suggests that changes in dopaminergic system in HD precede the manifestation of clinical symptoms, contradicting the theory that hyperdopaminergic status in HD is a consequence of neurodegeneration in the striatum.

KEYWORDS:

Huntington’s disease; hyperdopaminergic status; neurotransmitter phenotype; substantia nigra; transgenic rat model; ventral tegmental area

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