Abnormal cortico-basal ganglia neurotransmission in a mouse model of L-DOPA-induced dyskinesia

Indriani Dwi Wahyu, Satomi Chiken, Taku Hasegawa, Hiromi Sano, Atsushi Nambu

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

L-3, 4-dihydroxyphenylalanine (L-DOPA) is an effective treatment for Parkinson's disease (PD); however, long-term treatment induces L-DOPA-induced dyskinesia (LID). To elucidate its pathophysiology, we developed a mouse model of LID by daily administration of L-DOPA to PD male ICR mice treated with 6-hydroxydopamine (6-OHDA), and recorded the spontaneous and cortically evoked neuronal activity in the external segment of the globus pallidus (GPe) and substantia nigra pars reticulata (SNr), the connecting and output nuclei of the basal ganglia, respectively, in awake conditions. Spontaneous firing rates of GPe neurons were decreased in the dyskinesia-off state (_24 h after L-DOPA injection) and increased in the dyskinesia-on state (20-100 min after L-DOPA injection while showing dyskinesia), while those of SNr neurons showed no significant changes. GPe and SNr neurons showed bursting activity and low-frequency oscillation in the PD, dyskinesia-off, and dyskinesia-on states. In the GPe, cortically evoked late excitation was increased in the PD and dyskinesia-off states but decreased in the dyskinesia- on state. In the SNr, cortically evoked inhibition was largely suppressed, and monophasic excitation became dominant in the PD state. Chronic L-DOPA treatment partially recovered inhibition and suppressed late excitation in the dyskinesia-off state. In the dyskinesia-on state, inhibition was further enhanced, and late excitation was largely suppressed. Cortically evoked inhibition and late excitation in the SNr are mediated by the cortico-striato-SNr direct and cortico-striato-GPe-subthalamo-SNr indirect pathways, respectively. Thus, in the dyskinesia-on state, signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed, underlying LID.

Original languageEnglish
Pages (from-to)2668-2683
Number of pages16
JournalJournal of Neuroscience
Volume41
Issue number12
DOIs
Publication statusPublished - 24-03-2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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