title: Involvement of Striatal Cholinergic Interneurons and M1 and M4 Muscarinic Receptors in Motor Symptoms of Parkinson's Disease.
abstract: Over the last decade, striatal cholinergic interneurons (ChIs) have reemerged as key actors in the pathophysiology of basal-ganglia-related movement disorders. However, the mechanisms involved are still unclear. In this study, we address the role of ChI activity in the expression of parkinsonian-like motor deficits in a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion model using optogenetic and pharmacological approaches. Dorsal striatal photoinhibition of ChIs in lesioned ChAT(cre/cre) mice expressing halorhodopsin in ChIs reduces akinesia, bradykinesia, and sensorimotor neglect. Muscarinic acetylcholine receptor (mAChR) blockade by scopolamine produces similar anti-parkinsonian effects. To decipher which of the mAChR subtypes provides these beneficial effects, systemic and intrastriatal administration of the selective M1 and M4 mAChR antagonists telenzepine and tropicamide, respectively, were tested in the same model of Parkinson's disease. The two compounds alleviate 6-OHDA lesion-induced motor deficits. Telenzepine produces its beneficial effects by blocking postsynaptic M1 mAChRs expressed on medium spiny neurons (MSNs) at the origin of the indirect striatopallidal and direct striatonigral pathways. The anti-parkinsonian effects of tropicamide were almost completely abolished in mutant lesioned mice that lack M4 mAChRs specifically in dopamine D1-receptor-expressing neurons, suggesting that postsynaptic M4 mAChRs expressed on direct MSNs mediate the antiakinetic action of tropicamide. The present results show that altered cholinergic transmission via M1 and M4 mAChRs of the dorsal striatum plays a pivotal role in the occurrence of motor symptoms in Parkinson's disease.
  
  
  
  The striatum, where dopaminergic and cholinergic systems interact, is the pivotal structure of basal ganglia involved in pathophysiological changes underlying Parkinson's disease. Here, using optogenetic and pharmacological approaches, we investigated the involvement of striatal cholinergic interneurons (ChIs) and muscarinic receptor subtypes (mAChRs) in the occurrence of a wide range of motor deficits such as akinesia, bradykinesia, motor coordination, and sensorimotor neglect after unilateral nigrostriatal 6-hydroxydopamine lesion in mice. Our results show that photoinhibition of ChIs in the dorsal striatum and pharmacological blockade of muscarinic receptors, specifically postsynaptic M1 and M4 mAChRs, alleviate lesion-induced motor deficits. The present study points to these receptor subtypes as potential targets for the symptomatic treatment of parkinsonian-like motor symptoms.
authors: Aix Marseille University, Centre National de la Recherche Scientifique, LNC, FR3C, 13331 Marseille cdx 03, France.
authors: Samira
authors: 0000-0003-2058-4915
authors: S
authors: Ztaou
authors: Aix Marseille University, Centre National de la Recherche Scientifique, IBDM, 13288 Marseille cdx 09, France, and.
authors: Nicolas
authors: N
authors: Maurice
authors: Aix Marseille University, Centre National de la Recherche Scientifique, LNC, FR3C, 13331 Marseille cdx 03, France.
authors: Jeremy
authors: J
authors: Camon
authors: Aix Marseille University, Centre National de la Recherche Scientifique, NICN, 13344 Marseille cdx 15, France.
authors: Gaëlle
authors: G
authors: Guiraudie-Capraz
authors: Aix Marseille University, Centre National de la Recherche Scientifique, IBDM, 13288 Marseille cdx 09, France, and.
authors: Lydia
authors: L
authors: Kerkerian-Le Goff
authors: Aix Marseille University, Centre National de la Recherche Scientifique, IBDM, 13288 Marseille cdx 09, France, and.
authors: Corinne
authors: C
authors: Beurrier
authors: Aix Marseille University, Centre National de la Recherche Scientifique, LNC, FR3C, 13331 Marseille cdx 03, France.
authors: Martine
authors: M
authors: Liberge
authors: Aix Marseille University, Centre National de la Recherche Scientifique, LNC, FR3C, 13331 Marseille cdx 03, France, marianne.amalric@univ-amu.fr.
authors: Marianne
authors: 0000-0002-9915-6763
authors: M
authors: Amalric
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D059329:Cholinergic Neurons / Q000502:physiology*; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D007839:Functional Laterality; D005838:Genotype; D018476:Hypokinesia / Q000139:chemically induced; D007980:Levodopa / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D062308:Optogenetics; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D043588:Receptor, Muscarinic M4 / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D018663:Adrenergic Agents; D008164:Luminescent Proteins; D043643:Receptor, Muscarinic M1; D043588:Receptor, Muscarinic M4; D007980:Levodopa; D016627:Oxidopamine; D000661:Amphetamine; D002795:Choline O-Acetyltransferase
keywords: Parkinson's disease; basal ganglia; cholinergic interneurons; motor symptoms; muscarinic receptors; striatum