@article{eb9913d0032e4815a34e29c0b82e0772,
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.",
author = "Weixing Shen and Plotkin, {Joshua L.} and Veronica Francardo and Ko, {Wai Kin D.} and Zhong Xie and Qin Li and Tim Fieblinger and J{\"u}rgen Wess and Neubig, {Richard R.} and Lindsley, {Craig W.} and Conn, {P. Jeffrey} and Paul Greengard and Erwan Bezard and Cenci, {M. Angela} and Surmeier, {D. James}",
note = "Funding Information: This work was supported by the Michael J. Fox Foundation to W.S., D.J.S., the NIH NS034696 and MH074866 to D.J.S., the JPB Foundation to D.J.S., P.G., the USAMRAA grant W81XWH-09-1-0402 to P.G.; by the NIH Intramural Research Program to J.W.; by the grant to R.R.N. from NIH DA023252; by the grants to P.J.C. and C.W.L. from the NIH MH073676 and NS071669; by the grants from Association France Parkinson, the Foundation de France, and LABEX BRAIN ANR-10-LABX-43 to E.B.; and by the grants to M.A.C. from Swedish governmental funding of clinical research (grant 43301-ALF), the Basal Ganglia Disorders Linnaeus Consortium (BAGADILICO), the Swedish Research Council, the Swedish Foundation for International Cooperation in Research and Higher Education (STINT), and the Olle Engkvist Foundation. We thank Shenyu Zhai and Savio Chan for their comments on the manuscript and Sasha Ulrich for technical assistance. P.J.C. and C.W.L. receive research support from AstraZeneca and are inventors on patents that protect multiple classes of M4R PAMs. ",
year = "2015",
month = nov,
day = "18",
doi = "10.1016/j.neuron.2015.10.039",
language = "English (US)",
volume = "88",
pages = "762--773",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "4",
}