title: Striatal cholinergic cell ablation attenuates L-DOPA induced dyskinesia in Parkinsonian mice.
abstract: 3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia (LID) is a debilitating side effect of long-term dopamine replacement therapy in Parkinson's Disease. At present, there are few therapeutic options for treatment of LID and mechanisms contributing to the development and maintenance of these drug-induced motor complications are not well understood. We have previously shown that pharmacological reduction of cholinergic tone attenuates the expression of LID in parkinsonian mice with established dyskinesia after chronic L-DOPA treatment. The present study was undertaken to provide anatomically specific evidence for the role of striatal cholinergic interneurons by ablating them before initiation of L-DOPA treatment and determining whether it decreases LID. We used a novel approach to ablate striatal cholinergic interneurons (ChIs) via Cre-dependent viral expression of the diphtheria toxin A subunit (DT-A) in hemiparkinsonian transgenic mice expressing Cre recombinase under control of the choline acetyltransferase promoter. We show that Cre recombinase-mediated DT-A ablation selectively eliminated ChIs when injected into striatum. The depletion of ChIs markedly attenuated LID without compromising the therapeutic efficacy of L-DOPA. These results provide evidence that ChIs play a key and selective role in LID and that strategies to reduce striatal cholinergic tone may represent a promising approach to decreasing L-DOPA-induced motor complications in Parkinson's disease.
authors.affiliation: Department of Neurology, The University of Chicago, Chicago, Illinois 60637, and Department of Neurology, Columbia University, New York, New York 10032.
authors.forename: Lisa
authors.initials: L
authors.lastname: Won
authors.forename: Yunmin
authors.initials: Y
authors.lastname: Ding
authors.forename: Pardeep
authors.initials: P
authors.lastname: Singh
authors.forename: Un Jung
authors.initials: UJ
authors.lastname: Kang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D003714:Denervation; D004167:Diphtheria Toxin / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology / Q000628:therapy*; D006892:Hydroxydopamines / Q000633:toxicity; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007980:Levodopa / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017072:Neostriatum / Q000166:cytology / Q000502:physiology*; D010275:Parasympathetic Nervous System / Q000166:cytology / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000503:physiopathology / Q000628:therapy*
chemical_list: D000978:Antiparkinson Agents; D018076:DNA, Complementary; D004167:Diphtheria Toxin; D006892:Hydroxydopamines; D007980:Levodopa
keywords: Parkinson's disease; behavior; cholinergic; diphtheria toxin; dyskinesia; striatum