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

Shen, Weixing; Plotkin, Joshua L; Francardo, Veronica LU ; Ko, Wai Kin D; Xie, Zhong; Li, Qin; Fieblinger, Tim LU ; Wess, Jürgen; Neubig, Richard R and Lindsley, Craig W, et al. (2015) In Neuron 88(4). p.762-773
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... (More)
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. (Less)
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type
Contribution to journal
publication status
published
subject
in
Neuron
volume
88
issue
4
pages
762 - 773
publisher
Cell Press
external identifiers
  • pmid:26590347
  • wos:000365765900016
  • scopus:84954519551
ISSN
0896-6273
DOI
10.1016/j.neuron.2015.10.039
language
English
LU publication?
yes
id
55c61c56-d73a-4d89-8cce-7bc7c907f9f0 (old id 8234964)
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http://www.ncbi.nlm.nih.gov/pubmed/26590347?dopt=Abstract
date added to LUP
2015-12-06 12:04:59
date last changed
2017-11-19 03:02:39
@article{55c61c56-d73a-4d89-8cce-7bc7c907f9f0,
  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       = {Shen, Weixing and Plotkin, Joshua L and Francardo, Veronica and Ko, Wai Kin D and Xie, Zhong and Li, Qin and Fieblinger, Tim and Wess, Jürgen and Neubig, Richard R and Lindsley, Craig W and Conn, P Jeffrey and Greengard, Paul and Bezard, Erwan and Cenci Nilsson, Angela and Surmeier, D James},
  issn         = {0896-6273},
  language     = {eng},
  number       = {4},
  pages        = {762--773},
  publisher    = {Cell Press},
  series       = {Neuron},
  title        = {M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia.},
  url          = {http://dx.doi.org/10.1016/j.neuron.2015.10.039},
  volume       = {88},
  year         = {2015},
}