Molecular adaptations of striatal spiny projection neurons during levodopa-induced dyskinesia
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Heiman-2014-Molecular adaptation.pdf
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Author(s)
Heiman, Myriam
Heilbut, Adrian
Francardo, Veronica
Kulicke, Ruth
Fenster, Robert
Kolaczyk, Eric D.
Mesirov, Jill P.
Surmeier, Dalton J.
Cenci, M. Angela
Greengard, Paul
Date Issued
March 2014
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Heiman, M., A. Heilbut, V. Francardo, R. Kulicke, R. J. Fenster, E. D. Kolaczyk, J. P. Mesirov, D. J. Surmeier, M. A. Cenci, and P. Greengard. “Molecular Adaptations of Striatal Spiny Projection Neurons During Levodopa-Induced Dyskinesia.” Proceedings of the National Academy of Sciences 111, no. 12 (March 5, 2014): 4578–4583.
Version
Final published version
Abstract
Levodopa treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). Although it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type–specific gene-expression changes that occur in subclasses of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes, the expression of which is correlated with levodopa dose, many of which are under the control of activator protein-1 and ERK signaling. Despite homeostatic adaptations involving several signaling modulators, activator protein-1–dependent gene expression remains highly dysregulated in direct pathway SPNs upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
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DOI of Published Version
https://doi.org/10.1073/pnas.1401819111
