Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models
Parkinsonian symptoms arise due to over-activity of the indirect striatal output pathway, and under-activity of the direct striatal output pathway. l-DOPA-induced dyskinesia (LID) is caused when the opposite circuitry problems are established, with the indirect pathway becoming underactive, and the...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-11-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114002356 |
| _version_ | 1818352376716722176 |
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| author | Sherri L. Thiele Betty Chen Charlotte Lo Tracey S. Gertler Ruth Warre James D. Surmeier Jonathan M. Brotchie Joanne E. Nash |
| author_facet | Sherri L. Thiele Betty Chen Charlotte Lo Tracey S. Gertler Ruth Warre James D. Surmeier Jonathan M. Brotchie Joanne E. Nash |
| author_sort | Sherri L. Thiele |
| collection | DOAJ |
| description | Parkinsonian symptoms arise due to over-activity of the indirect striatal output pathway, and under-activity of the direct striatal output pathway. l-DOPA-induced dyskinesia (LID) is caused when the opposite circuitry problems are established, with the indirect pathway becoming underactive, and the direct pathway becoming over-active. Here, we define synaptic plasticity abnormalities in these pathways associated with parkinsonism, symptomatic benefits of l-DOPA, and LID. We applied spike-timing dependent plasticity protocols to cortico-striatal synapses in slices from 6-OHDA-lesioned mouse models of parkinsonism and LID, generated in BAC transgenic mice with eGFP targeting the direct or indirect output pathways, with and without l-DOPA present. In naïve mice, bidirectional synaptic plasticity, i.e. LTP and LTD, was induced, resulting in an EPSP amplitude change of approximately 50% in each direction in both striatal output pathways, as shown previously. In parkinsonism and dyskinesia, both pathways exhibited unidirectional plasticity, irrespective of stimulation paradigm. In parkinsonian animals, the indirect pathway only exhibited LTP (LTP protocol: 143.5 ± 14.6%; LTD protocol 177.7 ± 22.3% of baseline), whereas the direct pathway only showed LTD (LTP protocol: 74.3 ± 4.0% and LTD protocol: 63.3 ± 8.7%). A symptomatic dose of l-DOPA restored bidirectional plasticity on both pathways to levels comparable to naïve animals (Indirect pathway: LTP protocol: 124.4 ± 22.0% and LTD protocol: 52.1 ± 18.5% of baseline. Direct pathway: LTP protocol: 140.7 ± 7.3% and LTD protocol: 58.4 ± 6.0% of baseline). In dyskinesia, in the presence of l-DOPA, the indirect pathway exhibited only LTD (LTP protocol: 68.9 ± 21.3% and LTD protocol 52.0 ± 14.2% of baseline), whereas in the direct pathway, only LTP could be induced (LTP protocol: 156.6 ± 13.2% and LTD protocol 166.7 ± 15.8% of baseline). We conclude that normal motor control requires bidirectional plasticity of both striatal outputs, which underlies the symptomatic benefits of l-DOPA. Switching from bidirectional to unidirectional plasticity drives global changes in striatal pathway excitability, and underpins parkinsonism and dyskinesia. |
| first_indexed | 2024-12-13T18:52:39Z |
| format | Article |
| id | doaj.art-0e3d4e4c5e6e4ecd84c9c2d0a22e3be0 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T18:52:39Z |
| publishDate | 2014-11-01 |
| publisher | Elsevier |
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| series | Neurobiology of Disease |
| spelling | doaj.art-0e3d4e4c5e6e4ecd84c9c2d0a22e3be02022-12-21T23:34:54ZengElsevierNeurobiology of Disease1095-953X2014-11-0171334344Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse modelsSherri L. Thiele0Betty Chen1Charlotte Lo2Tracey S. Gertler3Ruth Warre4James D. Surmeier5Jonathan M. Brotchie6Joanne E. Nash7Centre for Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, CanadaCentre for Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, CanadaCentre for Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, CanadaDepartment of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USACentre for Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, CanadaDepartment of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USADivision of Brain Imaging & Behaviour Systems — Neuroscience, Toronto Western Research Institute, 399 Bathurst Street, Toronto, ON M5T 2S8, CanadaCentre for Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, Canada; Corresponding author. Fax: +1 416 287 7676.Parkinsonian symptoms arise due to over-activity of the indirect striatal output pathway, and under-activity of the direct striatal output pathway. l-DOPA-induced dyskinesia (LID) is caused when the opposite circuitry problems are established, with the indirect pathway becoming underactive, and the direct pathway becoming over-active. Here, we define synaptic plasticity abnormalities in these pathways associated with parkinsonism, symptomatic benefits of l-DOPA, and LID. We applied spike-timing dependent plasticity protocols to cortico-striatal synapses in slices from 6-OHDA-lesioned mouse models of parkinsonism and LID, generated in BAC transgenic mice with eGFP targeting the direct or indirect output pathways, with and without l-DOPA present. In naïve mice, bidirectional synaptic plasticity, i.e. LTP and LTD, was induced, resulting in an EPSP amplitude change of approximately 50% in each direction in both striatal output pathways, as shown previously. In parkinsonism and dyskinesia, both pathways exhibited unidirectional plasticity, irrespective of stimulation paradigm. In parkinsonian animals, the indirect pathway only exhibited LTP (LTP protocol: 143.5 ± 14.6%; LTD protocol 177.7 ± 22.3% of baseline), whereas the direct pathway only showed LTD (LTP protocol: 74.3 ± 4.0% and LTD protocol: 63.3 ± 8.7%). A symptomatic dose of l-DOPA restored bidirectional plasticity on both pathways to levels comparable to naïve animals (Indirect pathway: LTP protocol: 124.4 ± 22.0% and LTD protocol: 52.1 ± 18.5% of baseline. Direct pathway: LTP protocol: 140.7 ± 7.3% and LTD protocol: 58.4 ± 6.0% of baseline). In dyskinesia, in the presence of l-DOPA, the indirect pathway exhibited only LTD (LTP protocol: 68.9 ± 21.3% and LTD protocol 52.0 ± 14.2% of baseline), whereas in the direct pathway, only LTP could be induced (LTP protocol: 156.6 ± 13.2% and LTD protocol 166.7 ± 15.8% of baseline). We conclude that normal motor control requires bidirectional plasticity of both striatal outputs, which underlies the symptomatic benefits of l-DOPA. Switching from bidirectional to unidirectional plasticity drives global changes in striatal pathway excitability, and underpins parkinsonism and dyskinesia.http://www.sciencedirect.com/science/article/pii/S0969996114002356Parkinson's diseaseDyskinesiaBAC transgenic mouse modelsSlice electrophysiologyStriatumSynaptic plasticity |
| spellingShingle | Sherri L. Thiele Betty Chen Charlotte Lo Tracey S. Gertler Ruth Warre James D. Surmeier Jonathan M. Brotchie Joanne E. Nash Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models Neurobiology of Disease Parkinson's disease Dyskinesia BAC transgenic mouse models Slice electrophysiology Striatum Synaptic plasticity |
| title | Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models |
| title_full | Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models |
| title_fullStr | Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models |
| title_full_unstemmed | Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models |
| title_short | Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models |
| title_sort | selective loss of bi directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l dopa induced dyskinesia in mouse models |
| topic | Parkinson's disease Dyskinesia BAC transgenic mouse models Slice electrophysiology Striatum Synaptic plasticity |
| url | http://www.sciencedirect.com/science/article/pii/S0969996114002356 |
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