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

卷:71

Article

Thiele, Sherri L.¹  Chen, Betty¹  Lo, Charlotte¹  Gertler, Tracey S.³  Warre, Ruth¹  Surmeier, James D.³  Brotchie, Jonathan M.²  Nash, Joanne E.¹ 

[1] Univ Toronto Scarborough, Ctr Neurobiol Stress, Dept Biol Sci, Toronto, ON M1C 1A4, Canada

[2] Toronto Western Res Inst, Div Brain Imaging & Behav Syst Neurosci, Toronto, ON M5T 258, Canada

[3] Northwestern Univ, Feinberg Sch Med, Dept Physiol, Chicago, IL 60611 USA

关键词: Parkinson's disease;    Dyskinesia;    BAC transgenic mouse models;    Slice electrophysiology;    Striatum;    Synaptic plasticity;   

DOI  :  10.1016/j.nbd.2014.08.006

来源: Elsevier

【 摘 要 】

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 naive 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 naive 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. Crown Copyright (C) 2014 Published by Elsevier Inc. All rights reserved.

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