Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

NEUROBIOLOGY OF DISEASE

卷:91

Article

Bordia, Tanuja¹  Perez, Xiomara A.¹  Heiss, Jaime E.¹  Zhang, Danhui¹  Quik, Maryka¹ 

[1] SRI Int, Biosci Div, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA

关键词: ChAT-Cre;    ChR2;    Dyskinesias;    Nicotinic;    Optogenetics;    Parkinson's disease;    Striatum;   

DOI  :  10.1016/j.nbd.2016.02.019

来源: Elsevier

【 摘 要 】

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 intemeurons 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 2 h and LIDs rated. Continuous stimulation with a short duration optical pulse (1-5 ms) 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 (20 ms to 1 s) reduced LIDs to a similar extent as nicotine treatment (similar to 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. (C) 2016 Elsevier Inc. All rights reserved.

【 授权许可】

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