2. Academic Validation
  3. M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia

M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia

  • Neuron. 2015 Nov 18;88(4):762-73. doi: 10.1016/j.neuron.2015.10.039.
Weixing Shen 1,  Joshua L Plotkin 1,  Veronica Francardo 2,  Wai Kin D Ko 3,  Zhong Xie 1,  Qin Li 4,  Tim Fieblinger 2,  Jürgen Wess 5,  Richard R Neubig 6,  Craig W Lindsley 7,  P Jeffrey Conn 7,  Paul Greengard 8,  Erwan Bezard 3,  M Angela Cenci 2,  D James Surmeier 9
Affiliations

Affiliations

  • 1 Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 2 Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
  • 3 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.
  • 4 Motac Neuroscience, Manchester M13 9XX, UK.
  • 5 Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • 6 Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
  • 7 Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • 8 Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY 10065, USA.
  • 9 Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: [email protected].
PMID: 26590347 DOI: 10.1016/j.neuron.2015.10.039
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.

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