title: Lack of depotentiation at basal ganglia output neurons in PD patients with levodopa-induced dyskinesia.
abstract: Parkinson's disease (PD), characterized by the loss of dopaminergic nigrostriatal projections, is a debilitating neurodegenerative disease which produces bradykinesia, rigidity, tremor and postural instability. The dopamine precursor levodopa (L-Dopa) is the most effective treatment for the amelioration of PD signs and symptoms, but long-term administration can lead to disabling motor fluctuations and L-Dopa-induced dyskinesias. In animal models of PD, a form of plasticity called depotentiation, or the reversal of previous potentiation, is selectively lost after the development of dyskinetic movements following L-Dopa treatment. We investigated whether low frequency stimulation (LFS) in the globus pallidus internus (GPi) and substantia nigra pars reticulata (SNr) could induce depotentiation at synapses that had already undergone high frequency stimulation (HFS)-induced potentiation. To do so, we measured the field potentials (fEPs) evoked by stimulation from a nearby microelectrode in 28 patients undergoing implantation of deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN) or GPi. We found that GPi and SNr synapses in patients with less severe dyskinesia underwent greater depotentiation following LFS than in patients with more severe dyskinesia. This demonstration of impaired depotentiation in basal ganglia output nuclei in PD patients with dyskinesia is an important validation of animal models of levodopa-induced dyskinesia. The ability of a synapse to reverse previous potentiation may be crucial to the normal function of the BG, perhaps by preventing saturation of the storage capacity required in motor learning and optimal motor function. Loss of this ability at the output nuclei may underlie, or contribute to the cellular basis of dyskinetic movements.
authors.affiliation: Department of Physiology, University of Toronto, Canada. Electronic address: ianprescott@gmail.com.
authors.forename: I A
authors.initials: IA
authors.lastname: Prescott
authors.affiliation: Department of Physiology, University of Toronto, Canada.
authors.forename: L D
authors.initials: LD
authors.lastname: Liu
authors.affiliation: Department of Physiology, University of Toronto, Canada.
authors.forename: J O
authors.initials: JO
authors.lastname: Dostrovsky
authors.affiliation: Dept. of Surgery, Division of Neurosurgery, Toronto Western Research Institute, Canada; Krembil Neuroscience Centre, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Hodaie
authors.affiliation: Dept. of Surgery, Division of Neurosurgery, Toronto Western Research Institute, Canada; Krembil Neuroscience Centre, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Lozano
authors.affiliation: Department of Physiology, University of Toronto, Canada; Dept. of Surgery, Division of Neurosurgery, Toronto Western Research Institute, Canada; Krembil Neuroscience Centre, Canada.
authors.forename: W D
authors.initials: WD
authors.lastname: Hutchison
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000368:Aged; D000978:Antiparkinson Agents / Q000009:adverse effects; D001479:Basal Ganglia / Q000473:pathology*; D055592:Biophysical Phenomena / Q000187:drug effects / Q000502:physiology*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000473:pathology*; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D008839:Microelectrodes; D008875:Middle Aged; D009415:Nerve Net / Q000187:drug effects / Q000503:physiopathology; D009474:Neurons / Q000502:physiology*; D010300:Parkinson Disease / Q000188:drug therapy; D012720:Severity of Illness Index; D013223:Statistics as Topic
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa
keywords: Basal ganglia; Depotentiation; Globus pallidus; Microelectrodes; Parkinson's disease; Substantia nigra; Synaptic plasticity