Morphological and electrophysiological changes in intratelencephalic-type pyramidal neurons in the motor cortex of a rat model of levodopa-induced dyskinesia

Neurobiol Dis. 2014 Apr:64:142-9. doi: 10.1016/j.nbd.2013.12.014. Epub 2014 Jan 4.

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.

Keywords: 6-Hydroxydopamine; Animal model; Dyskinesia; Levodopa; Miniature excitatory postsynaptic currents; Motor cortex; Parkinson's disease; Plasticity; Spine; Whole-cell patch clamp.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / adverse effects*
  • Antiparkinson Agents / pharmacology
  • Dendritic Spines / pathology
  • Dendritic Spines / physiology
  • Dyskinesia, Drug-Induced / pathology*
  • Dyskinesia, Drug-Induced / physiopathology
  • Excitatory Postsynaptic Potentials
  • Levodopa / adverse effects*
  • Levodopa / pharmacology
  • Male
  • Motor Cortex / drug effects
  • Motor Cortex / pathology*
  • Motor Cortex / physiopathology
  • Neural Pathways / drug effects
  • Neural Pathways / pathology
  • Neural Pathways / physiopathology
  • Oxidopamine
  • Parkinsonian Disorders / drug therapy
  • Parkinsonian Disorders / pathology*
  • Parkinsonian Disorders / physiopathology
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / pathology*
  • Pyramidal Cells / physiopathology
  • Rats
  • Rats, Wistar
  • Telencephalon / drug effects
  • Telencephalon / pathology
  • Telencephalon / physiopathology

Substances

  • Antiparkinson Agents
  • Levodopa
  • Oxidopamine