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

Shen W, Plotkin JL, Francardo V, Ko WK, Xie Z, Li Q, Fieblinger T, Wess J, Neubig RR, Lindsley CW, Conn PJ, Greengard P, Bezard E, Cenci MA, Surmeier DJ
Neuron. 2015 88 (4): 762-73

PMID: 26590347 · PMCID: PMC4864040 · DOI:10.1016/j.neuron.2015.10.039

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.

Copyright © 2015 Elsevier Inc. All rights reserved.

MeSH Terms (20)

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

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