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: Weixing Shen, Joshua L Plotkin, Veronica Francardo, Wai Kin D Ko, Zhong Xie, Qin Li, Tim Fieblinger, Jürgen Wess, Richard R Neubig, Craig W Lindsley, P Jeffrey Conn, Paul Greengard, Erwan Bezard, M Angela Cenci, D James Surmeier
• Journal: Neuron (Neuron) Vol. 88 Issue 4 Pg. 762-73 (Nov 18 2015) ISSN: 1097-4199 [Electronic] United States
• PMID: 26590347 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Dopamine Agents
• RGS Proteins
• Receptor, Muscarinic M4
• RGS4 protein
• Glutamic Acid
• Levodopa

Topics

• Allosteric Regulation
• Animals
• Cerebral Cortex (metabolism)
• Disease Models, Animal
• Dopamine Agents (toxicity)
• Dyskinesia, Drug-Induced (etiology, metabolism)
• Glutamic Acid
• Levodopa (toxicity)
• Long-Term Potentiation (drug effects)
• Long-Term Synaptic Depression (drug effects)
• Macaca mulatta
• Mice
• Mice, Transgenic
• Neostriatum (drug effects, metabolism)
• Neuronal Plasticity (drug effects)
• Neurons
• Parkinsonian Disorders (drug therapy)
• RGS Proteins (metabolism)
• Receptor, Muscarinic M4 (metabolism)
• Signal Transduction