Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA
- Columbia University, United States
- New York University-Langone Medical Center, United States
- NYU Langone Health, United States
Abstract
Changes in striatal cholinergic interneuron (ChI) activity are thought to contribute to Parkinson's disease pathophysiology and dyskinesia from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, but the physiological basis of these changes is unknown. We find that dopamine lesion decreases the spontaneous firing rate of ChIs, whereas chronic treatment with L-DOPA of lesioned mice increases baseline ChI firing rates to levels beyond normal activity. The effect of dopamine loss on ChIs was due to decreased currents of both hyperpolarization-activated cyclic nucleotide-gated (HCN) and small conductance calcium-activated potassium (SK) channels. L-DOPA reinstatement of dopamine normalized HCN activity, but SK current remained depressed. Pharmacological blockade of HCN and SK activities mimicked changes in firing, confirming that these channels are responsible for the molecular adaptation of ChIs to dopamine loss and chronic L-DOPA treatment. These findings suggest that targeting ChIs with channel-specific modulators may provide therapeutic approaches for alleviating L-DOPA-induced dyskinesia in PD patients.
Data availability
All data generated for analyzed during this study are included in the manuscript and supporting files. Source data file has been provided for Fig 1-5 and Supp Fig 1-3.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (R01NS101982)
- Un Jung Kang
National Institute of Neurological Disorders and Stroke (R01NS075222)
- Eugene V Mosharov
National Institute of Neurological Disorders and Stroke (R01DA007418)
- David Sulzer
The JBP foundation
- David Sulzer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jun Ding, Stanford University, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#08-133) of the University of Arizona. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Minnesota (Permit Number: 27-2956). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.
Version history
- Received: March 13, 2020
- Accepted: July 17, 2020
- Accepted Manuscript published: July 20, 2020 (version 1)
- Version of Record published: July 24, 2020 (version 2)
- Version of Record updated: July 27, 2020 (version 3)
Copyright
© 2020, Choi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA
eLife 9:e56920.
https://doi.org/10.7554/eLife.56920
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