title: Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias.
abstract: L-dopa-induced dyskinesias (LIDs) are a serious complication of L-dopa therapy for Parkinson's disease. Emerging evidence indicates that the nicotinic cholinergic system plays a role in LIDs, although the pathways and mechanisms are poorly understood. Here we used optogenetics to investigate the role of striatal cholinergic interneurons in LIDs. Mice expressing cre-recombinase under the control of the choline acetyltransferase promoter (ChAT-Cre) were lesioned by unilateral injection of 6-hydroxydopamine. AAV5-ChR2-eYFP or AAV5-control-eYFP was injected into the dorsolateral striatum, and optical fibers implanted. After stable virus expression, mice were treated with L-dopa. They were then subjected to various stimulation protocols for 2h and LIDs rated. Continuous stimulation with a short duration optical pulse (1-5ms) enhanced LIDs. This effect was blocked by the general muscarinic acetylcholine receptor (mAChR) antagonist atropine indicating it was mAChR-mediated. By contrast, continuous stimulation with a longer duration optical pulse (20ms to 1s) reduced LIDs to a similar extent as nicotine treatment (~50%). The general nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine blocked the decline in LIDs with longer optical pulses showing it was nAChR-mediated. None of the stimulation regimens altered LIDs in control-eYFP mice. Lesion-induced motor impairment was not affected by optical stimulation indicating that cholinergic transmission selectively regulates LIDs. Longer pulse stimulation increased the number of c-Fos expressing ChAT neurons, suggesting that changes in this immediate early gene may be involved. These results demonstrate that striatal cholinergic interneurons play a critical role in LIDs and support the idea that nicotine treatment reduces LIDs via nAChR desensitization.
authors.affiliation: Bioscience Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025.
authors.forename: Tanuja
authors.initials: T
authors.lastname: Bordia
authors.affiliation: Bioscience Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025.
authors.forename: Xiomara A
authors.initials: XA
authors.lastname: Perez
authors.affiliation: Bioscience Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025.
authors.forename: Jaime
authors.initials: J
authors.lastname: Heiss
authors.affiliation: Bioscience Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025.
authors.forename: Danhui
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Bioscience Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025.
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
mesh_terms: D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D007395:Interneurons / Q000187:drug effects* / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D051379:Mice; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D062308:Optogenetics / Q000379:methods
chemical_list: D018722:Nicotinic Agonists; D007980:Levodopa; D009538:Nicotine; D002795:Choline O-Acetyltransferase
keywords: ChAT-Cre; ChR2; Dyskinesias; Nicotinic; Optogenetics; Parkinson's disease; Striatum