title: M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia.
abstract: A balanced interaction between dopaminergic and cholinergic signaling in the striatum is critical to goal-directed behavior. But how this interaction modulates corticostriatal synaptic plasticity underlying learned actions remains unclear--particularly in direct-pathway spiny projection neurons (dSPNs). Our studies show that in dSPNs, endogenous cholinergic signaling through M4 muscarinic receptors (M4Rs) promoted long-term depression of corticostriatal glutamatergic synapses, by suppressing regulator of G protein signaling type 4 (RGS4) activity, and blocked D1 dopamine receptor dependent long-term potentiation (LTP). Furthermore, in a mouse model of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease (PD), boosting M4R signaling with positive allosteric modulator (PAM) blocked aberrant LTP in dSPNs, enabled LTP reversal, and attenuated dyskinetic behaviors. An M4R PAM also was effective in a primate LID model. Taken together, these studies identify an important signaling pathway controlling striatal synaptic plasticity and point to a novel pharmacological strategy for alleviating LID in PD patients.
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Weixing
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Plotkin
authors.affiliation: Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
authors.forename: Veronica
authors.initials: V
authors.lastname: Francardo
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Motac Neuroscience, Manchester M13 9XX, UK.
authors.forename: Wai Kin D
authors.initials: WK
authors.lastname: Ko
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Motac Neuroscience, Manchester M13 9XX, UK.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
authors.forename: Tim
authors.initials: T
authors.lastname: Fieblinger
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY 10065, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Motac Neuroscience, Manchester M13 9XX, UK.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.affiliation: Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
authors.forename: M Angela
authors.initials: MA
authors.lastname: Cenci
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: j-surmeier@northwestern.edu.
authors.forename: D James
authors.initials: DJ
authors.lastname: Surmeier
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000633:toxicity*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000378:metabolism*; D018698:Glutamic Acid; D007980:Levodopa / Q000633:toxicity*; D017774:Long-Term Potentiation / Q000187:drug effects; D036881:Long-Term Synaptic Depression / Q000187:drug effects; D008253:Macaca mulatta; D051379:Mice; D008822:Mice, Transgenic; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D020710:RGS Proteins / Q000378:metabolism*; D043588:Receptor, Muscarinic M4 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015259:Dopamine Agents; D020710:RGS Proteins; D043588:Receptor, Muscarinic M4; C098799:RGS4 protein; D018698:Glutamic Acid; D007980:Levodopa