title: Molecular adaptations of striatal spiny projection neurons during levodopa-induced dyskinesia.
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.
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
authors.forename: Myriam
authors.initials: M
authors.lastname: Heiman
authors.forename: Adrian
authors.initials: A
authors.lastname: Heilbut
authors.forename: Veronica
authors.initials: V
authors.lastname: Francardo
authors.forename: Ruth
authors.initials: R
authors.lastname: Kulicke
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fenster
authors.forename: Eric D
authors.initials: ED
authors.lastname: Kolaczyk
authors.forename: Jill P
authors.initials: JP
authors.lastname: Mesirov
authors.forename: Dalton J
authors.initials: DJ
authors.lastname: Surmeier
authors.forename: M Angela
authors.initials: MA
authors.lastname: Cenci
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000235:genetics*; D015870:Gene Expression; D006706:Homeostasis; D007980:Levodopa / Q000009:adverse effects*; D051379:Mice
chemical_list: D007980:Levodopa; D004298:Dopamine