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.
journal_name
Proc Natl Acad Sci U S Aauthors
Cyr M,Beaulieu JM,Laakso A,Sotnikova TD,Yao WD,Bohn LM,Gainetdinov RR,Caron MGdoi
10.1073/pnas.1831768100keywords:
subject
Has Abstractpub_date
2003-09-16 00:00:00pages
11035-40issue
19eissn
0027-8424issn
1091-6490pii
1831768100journal_volume
100pub_type
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