Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias
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 th...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-07-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996116300419 |
| _version_ | 1819120140296388608 |
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| author | Tanuja Bordia Xiomara A. Perez Jaime E. Heiss Danhui Zhang Maryka Quik |
| author_facet | Tanuja Bordia Xiomara A. Perez Jaime E. Heiss Danhui Zhang Maryka Quik |
| author_sort | Tanuja Bordia |
| collection | DOAJ |
| description | 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 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 (~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. |
| first_indexed | 2024-12-22T06:15:56Z |
| format | Article |
| id | doaj.art-5a44146eb22a4d109e0dafbb5cc48753 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-22T06:15:56Z |
| publishDate | 2016-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-5a44146eb22a4d109e0dafbb5cc487532022-12-21T18:36:06ZengElsevierNeurobiology of Disease1095-953X2016-07-01914758Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesiasTanuja Bordia0Xiomara A. Perez1Jaime E. Heiss2Danhui Zhang3Maryka Quik4Bioscience Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USABioscience Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USABioscience Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USABioscience Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USACorresponding author at: Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USA.; Bioscience Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USAL-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 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 (~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.http://www.sciencedirect.com/science/article/pii/S0969996116300419ChAT-CreChR2DyskinesiasNicotinicOptogeneticsParkinson's disease |
| spellingShingle | Tanuja Bordia Xiomara A. Perez Jaime E. Heiss Danhui Zhang Maryka Quik Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias Neurobiology of Disease ChAT-Cre ChR2 Dyskinesias Nicotinic Optogenetics Parkinson's disease |
| title | Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias |
| title_full | Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias |
| title_fullStr | Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias |
| title_full_unstemmed | Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias |
| title_short | Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias |
| title_sort | optogenetic activation of striatal cholinergic interneurons regulates l dopa induced dyskinesias |
| topic | ChAT-Cre ChR2 Dyskinesias Nicotinic Optogenetics Parkinson's disease |
| url | http://www.sciencedirect.com/science/article/pii/S0969996116300419 |
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