ArticleScience advances2024
Reduced striatal M4-cholinergic signaling following dopamine loss contributes to parkinsonian and l-DOPA-induced dyskinetic behaviors.
Article in Science advances, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Striatal cholinergic and dopaminergic driven astrocyte CabioRxiv : the preprint server for biology · 2026Article
- Dorsal striatal circuit mechanisms contributing to astrocyte modulation of alcohol-related behaviors.bioRxiv : the preprint server for biology · 2026Article
- The central cholinergic system as a therapeutic target in Parkinson's disease.Journal of Parkinson's disease · 2026Review
- Neurotransmitter Dysregulation in Parkinson's Disease: Pathophysiological Insights and Therapeutic Perspectives.ACS chemical neuroscience · 2026Review
- Synergistic Effects of Plant Polysaccharides and Probiotics: A Novel Dietary Approach for Parkinson's Disease Intervention.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Decoding GPCR signaling in living cells to advance early therapeutic discovery for neurological disorders.Frontiers in molecular neuroscience · 2026Review
- Treadmill exercise rescues motor deficits in parkinsonian mice by modulating striatal D2-MSN activity: evidence from calcium imaging and chemogenetics.Frontiers in systems neuroscience · 2026Article
- Dopamine 2 receptor ablation from cholinergic neurons attenuates L-DOPA induced dyskinesias.Frontiers in aging neuroscience · 2026Article
- Article
- Epigenetic regulation of cocaine intake through dopaminergic control of cholinergic interneurons in male mice.Nature communications · 2025Article
- State-dependent modulation of spiny projection neurons controls levodopa-induced dyskinesia in a mouse model of Parkinson's disease.Science advances · 2025Article
- Levodopa Disrupts Activity Patterns and Encoding of Movement in Striatal Cholinergic Interneurons of Behaving Mice.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- The role of L-DOPA in neurological and neurodegenerative complications: a review.Molecular and cellular biochemistry · 2025Review
- Postsynaptic adaptations in direct pathway muscarinic M4-receptor signaling follow the temporal and regional pattern of dopaminergic degeneration.NPJ Parkinson's disease · 2025Article
- Does Dysregulation Of The Indirect Pathway Contribute To The Pathophysiology Of Catatonia Through Neurotransmitter Imbalance?Clinical neuropsychiatry · 2025Article
- Repetitive Levodopa Treatment Drives Cell Type-Specific Striatal Adaptations Associated With Progressive Dyskinesia in Parkinsonian Mice.bioRxiv : the preprint server for biology · 2025Article
- State-dependent modulation of spiny projection neurons controls levodopa-induced dyskinesia in a mouse model of Parkinson's disease.bioRxiv : the preprint server for biology · 2025Article
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2 authors.
Funding
Abstract
A dynamic equilibrium between dopamine and acetylcholine (ACh) is essential for striatal circuitry and motor function, as imbalances are associated with Parkinson's disease (PD) and levodopa-induced dyskinesia (LID). Conventional theories posit that cholinergic signaling is pathologically elevated in PD as a result of increased ACh release, which contributes to motor deficits. However, using approaches to measure receptor-mediated signaling, we found that, rather than the predicted enhancement, the strength of cholinergic transmission at muscarinic M4 receptor synapses on direct pathway medium spiny neurons was decreased in dopamine-depleted mice. This adaptation was due to a reduced postsynaptic M4 receptor function, resulting from down-regulated receptors and downstream signaling. Restoring M4 transmission unexpectedly led to a partial alleviation of motor deficits and LID dyskinetic behavior, revealing an unexpected prokinetic effect in addition to the canonical antikinetic role of M4 receptors. These findings indicate that decreased M4 function differentially contributes to parkinsonian and LID pathophysiology, representing a promising target for therapeutic intervention.
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