title: Morphological and electrophysiological changes in intratelencephalic-type pyramidal neurons in the motor cortex of a rat model of levodopa-induced dyskinesia.
abstract: Levodopa-induced dyskinesia (LID) is a major complication of long-term dopamine replacement therapy for Parkinson's disease, and becomes increasingly problematic in the advanced stage of the disease. Although the cause of LID still remains unclear, there is accumulating evidence from animal experiments that it results from maladaptive plasticity, resulting in supersensitive excitatory transmission at corticostriatal synapses. Recent work using transcranial magnetic stimulation suggests that the motor cortex displays the same supersensitivity in Parkinson's disease patients with LID. To date, the cellular mechanisms underlying the abnormal cortical plasticity have not been examined. The morphology of the dendritic spines has a strong relationship to synaptic plasticity. Therefore, we explored the spine morphology of pyramidal neurons in the motor cortex in a rat model of LID. We used control rats, 6-hydroxydopamine-lesioned rats (a model of Parkinson's disease), 6-hydroxydopamine-lesioned rats chronically treated with levodopa (a model of LID), and control rats chronically treated with levodopa. Because the direct pathway of the basal ganglia plays a central role in the development of LID, we quantified the density and size of dendritic spines in intratelencephalic (IT)-type pyramidal neurons in M1 cortex that project to the striatal medium spiny neurons in the direct pathway. The spine density was not different among the four groups. In contrast, spine size became enlarged in the Parkinson's disease and LID rat models. The enlargement was significantly greater in the LID model than in the Parkinson's disease model. This enlargement of the spines suggests that IT-type pyramidal neurons acquire supersensitivity to excitatory stimuli. To confirm this possibility, we monitored miniature excitatory postsynaptic currents (mEPSCs) in the IT-type pyramidal neurons in M1 cortex using whole-cell patch clamp. The amplitude of the mEPSCs was significantly increased in the LID model compared with the control. This indicates that the IT-type pyramidal neurons become hyperexcited in the LID model, paralleling the enlargement of spines. Thus, spine enlargement and the resultant hyperexcitability of IT-type pyramidal neurons in M1 cortex might contribute to the abnormal cortical neuronal plasticity in LID.
authors.affiliation: Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan; Department of Neurophysiology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan. Electronic address: lacote19thg@gmail.com.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Neurophysiology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Yamada
authors.affiliation: Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan; Department of Neurophysiology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Nishijima
authors.affiliation: Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan; Department of Neurophysiology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Arai
authors.affiliation: Department of Neurophysiology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Migita
authors.affiliation: Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Baba
authors.affiliation: Department of Neurophysiology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueno
authors.affiliation: Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan; Department of Neurophysiology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tomiyama
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000494:pharmacology; D049229:Dendritic Spines / Q000473:pathology / Q000502:physiology; D004409:Dyskinesia, Drug-Induced / Q000473:pathology* / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials; D007980:Levodopa / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D009044:Motor Cortex / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D013687:Telencephalon / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa; D016627:Oxidopamine
keywords: 6-Hydroxydopamine; Animal model; Dyskinesia; Levodopa; Miniature excitatory postsynaptic currents; Motor cortex; Parkinson's disease; Plasticity; Spine; Whole-cell patch clamp