M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia.
Neuron. 2015-11-01; 88(4): 762-773
DOI: 10.1016/j.neuron.2015.10.039
Read on PubMed
1. Neuron. 2015 Nov 18;88(4):762-73. doi: 10.1016/j.neuron.2015.10.039.
M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in
Models of L-DOPA-Induced Dyskinesia.
Shen W(1), Plotkin JL(1), Francardo V(2), Ko WK(3), Xie Z(1), Li Q(4), Fieblinger
T(2), Wess J(5), Neubig RR(6), Lindsley CW(7), Conn PJ(7), Greengard P(8), Bezard
E(3), Cenci MA(2), Surmeier DJ(9).
Author information:
(1)Department of Physiology, Feinberg School of Medicine, Northwestern
University, Chicago, IL 60611, USA.
(2)Basal Ganglia Pathophysiology Unit, Department of Experimental Medical
Science, Lund University, 221 84 Lund, Sweden.
(3)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR
5293, F-33000 Bordeaux, France; Motac Neuroscience, Manchester M13 9XX, UK.
(4)Motac Neuroscience, Manchester M13 9XX, UK.
(5)Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National
Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of
Health, Bethesda, MD 20892, USA.
(6)Department of Pharmacology and Toxicology, Michigan State University, East
Lansing, MI 48824, USA.
(7)Department of Pharmacology and Vanderbilt Center for Neuroscience Drug
Discovery, Vanderbilt University, Nashville, TN 37232, USA.
(8)Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New
York, NY 10065, USA.
(9)Department of Physiology, Feinberg School of Medicine, Northwestern
University, Chicago, IL 60611, USA. Electronic address:
.
Comment in
Neuron. 2015 Nov 18;88(4):621-3.
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.
DOI: 10.1016/j.neuron.2015.10.039
PMCID: PMC4864040
PMID: 26590347 [Indexed for MEDLINE]