M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/8234964
- author
- organization
- publishing date
- 2015
- 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
- pmid:26590347
- 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)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/26590347?dopt=Abstract
- date added to LUP
- 2016-04-01 09:56:30
- date last changed
- 2022-05-17 18:19:37
@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}}, doi = {{10.1016/j.neuron.2015.10.039}}, volume = {{88}}, year = {{2015}}, }