Sustained elevation of extracellular dopamine causes motor dysfunction and selective degeneration of striatal GABAergic neurons.

Content Provider	Semantic Scholar
Author	Cyr, Michel Beaulieu, Jean-Martin Laakso, Aki Sotnikova, Tatyana D. Yao, Wei-Dong Bohn, Laura M. Gainetdinov, Raul R. Caron, Marc G.
Copyright Year	2003
Abstract	Dopamine is believed to contribute to the degeneration of dopamine-containing neurons in the brain. However, whether dopamine affects the survival of other neuronal populations has remained unclear. Here we document that mice with persistently elevated extracellular dopamine, resulting from inactivation of the dopamine transporter gene, sporadically develop severe symptoms of dyskinesia concomitant with apoptotic death of striatal dopamine-responsive gamma-aminobutyric acidergic neurons. Chronic inhibition of dopamine synthesis prevents the appearance of motor dysfunction. The neuronal death is associated with overactivation of dopaminergic signaling as evidenced by the robust up-regulation of striatal DeltaFosB, cyclin-dependent kinase 5, and p35. Moreover, hyperphosphorylation of the tau protein, a phenomenon associated with the activation of cyclin-dependent kinase 5 in several neurodegenerative disorders, is observed in symptomatic mice. These findings provide in vivo evidence that, in addition to its proposed role in the degeneration of dopamine neurons, dopamine can also contribute to the selective death of its target neurons via a previously unappreciated mechanism.
File Format	PDF HTM / HTML
DOI	10.1073/pnas.1831768100
PubMed reference number	12958210
Journal	Medline
Volume Number	100
Issue Number	19
Alternate Webpage(s)	http://www.pnas.org/content/100/19/11035.full.pdf?with-ds=yes
Journal	Proceedings of the National Academy of Sciences of the United States of America
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article