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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)762-773
Number of pages12
JournalNeuron
Volume88
Issue number4
DOIs
StatePublished - Nov 18 2015

ASJC Scopus subject areas

  • Neuroscience(all)

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