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.
abstract: 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.
authors.affiliation: Centre for Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, Canada.
authors.forename: Sherri L
authors.initials: SL
authors.lastname: Thiele
authors.affiliation: Centre for Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, Canada.
authors.forename: Betty
authors.initials: B
authors.lastname: Chen
authors.affiliation: Centre for Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, Canada.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lo
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Tracey S
authors.initials: TS
authors.lastname: Gertler
authors.affiliation: Centre for Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: Warre
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Surmeier
authors.affiliation: Division of Brain Imaging & Behaviour Systems - Neuroscience, Toronto Western Research Institute, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
authors.affiliation: Centre for Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, Canada. Electronic address: jnash@utsc.utoronto.ca.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Nash
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000978:Antiparkinson Agents / Q000009:adverse effects*; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000473:pathology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D007839:Functional Laterality; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D007980:Levodopa / Q000009:adverse effects*; D051379:Mice; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000473:pathology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy; D058905:Purinergic Agents / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D015259:Dopamine Agents; D058905:Purinergic Agents; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1; D049452:Green Fluorescent Proteins; D007980:Levodopa; D016627:Oxidopamine
keywords: BAC transgenic mouse models; Dyskinesia; Parkinson's disease; Slice electrophysiology; Striatum; Synaptic plasticity