Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson’s Disease
Open accessAbstract
Motor and cognitive functions depend on the coordinated interactions between dopamine (DA) and acetylcholine (ACh) at striatal synapses. Increased ACh availability was assumed to accompany DA deficiency based on the outcome of pharmacological treatments and measurements in animals that were critically depleted of DA. Using Slc6a3 DTR/+ diphtheria-toxin-sensitive mice, we demonstrate that a progressive and L-dopa-responsive DA deficiency reduces ACh availability and the transcription of hyperpolarization-activated cation (HCN) channels that encode the spike timing of ACh-releasing tonically active striatal interneurons (ChIs). Although the production and release of ACh and DA are reduced, the preponderance of ACh over DA contributes to the motor deficit. The increase in striatal ACh relative to DA is heightened via D1-type DA receptors that activate ChIs in response to DA release from residual axons. These results suggest that stabilizing the expression of HCN channels may improve ACh-DA reciprocity and motor function in Parkinson's disease (PD). VIDEO ABSTRACT.
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Cholinergic degeneration may be an important indicator for early cognitive impairment in PD.
“Neuropathological evidence suggests that cholinergic degeneration may be an important indicator for early cognitive impairment in PD [48-50].”
From QEEG Signatures are Associated with Nonmotor Dysfunctions in Parkinson's Disease and Atypical Parkinsonism: An Integrative Analysis (2023) · cites this paper as [48]
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- Authors
- McKinley, J. W., Shi, Z., Kawikova, I., Hur, M., Bamford, I. J., Sudarsana Devi, S. P., Vahedipour, A., Darvas, M., & Bamford, N. S.
- Affiliations
- Yale University (US)
- University of Washington (US)
- Corresponding author
- Bamford, Nigel S.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2019-09
- Volume
- 103
- Issue
- 6
- Pages
- 1056-1072.e6
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC7102938
- OpenAlex
- W2961568329
- Cited by
- 130
- References
- 76
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 20 · 2023: 19 · 2022: 27 · 2021: 21 · 2020: 16 · 2019: 4
- FWCI
- 11.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- dopamine deficiency, Parkinson's disease, striatal cholinergic interneurons, HCN channels, dopamine D1 receptor, motor impairment, L-DOPA, cholinergic depletion, diphtheria toxin, transcriptional regulation
- MeSH terms
- Acetylcholine, Amphetamine, Animals, Disease Models, Animal, Dopamine, Interneurons, Parkinson Disease, Transcription, Genetic, Dopamine Agents, Neostriatum, Receptors, Dopamine D1, Receptors, Dopamine D2, Cyclic AMP-Dependent Protein Kinases, Patch-Clamp Techniques, Dopamine Plasma Membrane Transport Proteins, Mice, Cholinergic Neurons, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
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