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Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson’s Disease

Neuron (Cambridge, Mass.), 2019-09, Vol.103 (6), p.1056-1072.e6 [Peer Reviewed Journal]

2019 Elsevier Inc. ;Copyright © 2019 Elsevier Inc. All rights reserved. ;2019. Elsevier Inc. ;ISSN: 0896-6273 ;EISSN: 1097-4199 ;DOI: 10.1016/j.neuron.2019.06.013 ;PMID: 31324539

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Title:
Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson’s Disease
Author: McKinley, Jonathan W. ; Shi, Ziqing ; Kawikova, Ivana ; Hur, Matthew ; Bamford, Ian J. ; Sudarsana Devi, Suma Priya ; Vahedipour, Annie ; Darvas, Martin ; Bamford, Nigel S.
Subjects: Acetylcholine ; Acetylcholine - metabolism ; Amphetamine - pharmacology ; Animals ; Axons ; Cholinergic Neurons - drug effects ; Cholinergic Neurons - metabolism ; Cholinergic Neurons - physiology ; Cognitive ability ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Dihydroxyphenylalanine ; Diphtheria ; diphtheria toxin ; Disease Models, Animal ; Dopamine ; Dopamine - deficiency ; Dopamine - metabolism ; dopamine acetylcholine ratio ; Dopamine Agents - pharmacology ; Dopamine D1 receptors ; dopamine depletion ; Dopamine Plasma Membrane Transport Proteins - genetics ; Dopamine receptors ; Drug therapy ; electrophysiology ; HCN channel ; Hyperpolarization ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - genetics ; Interneurons ; Interneurons - drug effects ; Interneurons - metabolism ; Interneurons - physiology ; Ion channels (cyclic nucleotide-gated) ; Levodopa ; Mice ; Movement disorders ; Neostriatum ; Neostriatum - cytology ; Neostriatum - drug effects ; Neostriatum - metabolism ; Neostriatum - physiopathology ; Neurodegenerative diseases ; Parkinson Disease - metabolism ; Parkinson Disease - physiopathology ; Parkinson's disease ; Parkinsons disease ; Patch-Clamp Techniques ; Probability distribution ; receptor ; Receptors, Dopamine D1 - metabolism ; Receptors, Dopamine D2 - metabolism ; RiboTag ; Transcription ; Transcription, Genetic
Is Part Of: Neuron (Cambridge, Mass.), 2019-09, Vol.103 (6), p.1056-1072.e6
Description: 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 Slc6a3DTR/+ 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). [Display omitted] [Display omitted] •Progressive dopamine deficiency reduces striatal cholinergic interneuron activity•The preponderance of acetylcholine over dopamine contributes to the motor deficit•Dopamine release worsens the imbalance between acetylcholine and dopamine•Targeted cholinergic therapy may improve motor dysfunction in parkinsonism McKinley et al. use a new model of Parkinson’s disease to show that a reduction in dopamine modifies the availability of acetylcholine within the striatum, suggesting that treatment of the disease requires restoration of the balance between these neurotransmitters.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0896-6273
EISSN: 1097-4199
DOI: 10.1016/j.neuron.2019.06.013
PMID: 31324539
Source: Cell Press Free Archives
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Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson’s Disease

2019 Elsevier Inc. ;Copyright © 2019 Elsevier Inc. All rights reserved. ;2019. Elsevier Inc. ;ISSN: 0896-6273 ;EISSN: 1097-4199 ;DOI: 10.1016/j.neuron.2019.06.013 ;PMID: 31324539

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