Involvement of Striatal Cholinergic Interneurons and M1 and M4 Muscarinic Receptors in Motor Symptoms of Parkinson's Disease.
Identifieur interne : 000251 ( Main/Exploration ); précédent : 000250; suivant : 000252Involvement of Striatal Cholinergic Interneurons and M1 and M4 Muscarinic Receptors in Motor Symptoms of Parkinson's Disease.
Auteurs : Samira Ztaou [France] ; Nicolas Maurice ; Jeremy Camon [France] ; Gaëlle Guiraudie-Capraz [France] ; Lydia Kerkerian-Le Goff ; Corinne Beurrier ; Martine Liberge [France] ; Marianne Amalric [France]Source :
- The Journal of neuroscience : the official journal of the Society for Neuroscience [ 1529-2401 ] ; 2016.
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.
DOI: 10.1523/JNEUROSCI.0873-16.2016
PubMed: 27581457
Affiliations:
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University, Centre National de la Recherche Scientifique, LNC, FR3C, 13331 Marseille cdx 03, France, marianne.amalric@univ-amu.fr.</nlm:affiliation><country wicri:rule="url">France</country><wicri:regionArea>Aix Marseille University, Centre National de la Recherche Scientifique, LNC, FR3C, 13331 Marseille cdx 03, France</wicri:regionArea><wicri:noRegion>France</wicri:noRegion><wicri:noRegion>France</wicri:noRegion></affiliation></author></analytic><series><title level="j">The Journal of neuroscience : the official journal of the Society for Neuroscience</title><idno type="eISSN">1529-2401</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>France</li></country><region><li>Provence-Alpes-Côte d'Azur</li></region><settlement><li>Marseille cdx 03</li><li>Marseille cdx 15</li></settlement></list><tree><noCountry><name sortKey="Beurrier, Corinne" sort="Beurrier, Corinne" uniqKey="Beurrier C" first="Corinne" last="Beurrier">Corinne Beurrier</name><name sortKey="Kerkerian Le Goff, Lydia" sort="Kerkerian Le Goff, Lydia" uniqKey="Kerkerian Le Goff L" first="Lydia" last="Kerkerian-Le Goff">Lydia Kerkerian-Le Goff</name><name sortKey="Maurice, Nicolas" sort="Maurice, Nicolas" uniqKey="Maurice N" first="Nicolas" last="Maurice">Nicolas Maurice</name></noCountry><country name="France"><region name="Provence-Alpes-Côte d'Azur"><name sortKey="Ztaou, Samira" sort="Ztaou, Samira" uniqKey="Ztaou S" first="Samira" last="Ztaou">Samira Ztaou</name></region><name sortKey="Amalric, Marianne" sort="Amalric, Marianne" uniqKey="Amalric M" first="Marianne" last="Amalric">Marianne Amalric</name><name sortKey="Camon, Jeremy" sort="Camon, Jeremy" uniqKey="Camon J" first="Jeremy" last="Camon">Jeremy Camon</name><name sortKey="Guiraudie Capraz, Gaelle" sort="Guiraudie Capraz, Gaelle" uniqKey="Guiraudie Capraz G" first="Gaëlle" last="Guiraudie-Capraz">Gaëlle Guiraudie-Capraz</name><name sortKey="Liberge, Martine" sort="Liberge, Martine" uniqKey="Liberge M" first="Martine" last="Liberge">Martine Liberge</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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