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Mechanisms of Dopamine D1 Receptor-Mediated ERK1/2 Activation in the Parkinsonian Striatum and Their Modulation by Metabotropic Glutamate Receptor Type 5

Authors :
Sabina Sandberg
David Engblom
Tim Fieblinger
M. Angela Cenci
Irene Sebastianutto
Cristina Alcacer
Zisis Bimpisidis
Natallia Maslava
Source :
The Journal of neuroscience : the official journal of the Society for Neuroscience; 34(13), pp 4728-4740 (2014)
Publication Year :
2014
Publisher :
Society for Neuroscience, 2014.

Abstract

In animal models of Parkinson′s disease, striatal overactivation of ERK1/2 via dopamine (DA) D1 receptors is the hallmark of a supersensitive molecular response associated with dyskinetic behaviors. Here we investigate the pathways involved in D1 receptor-dependent ERK1/2 activation using acute striatal slices from rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. Application of the dopamine D1-like receptor agonist SKF38393 induced ERK1/2 phosphorylation and downstream signaling in the DA-denervated but not the intact striatum. This response was mediated through a canonical D1R/PKA/MEK1/2 pathway and independent of ionotropic glutamate receptors but blocked by antagonists of L-type calcium channels. Coapplication of an antagonist of metabotropic glutamate receptor type 5 (mGluR5) or its downstream signaling molecules (PLC, PKC, IP3receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmedin vivoin 6-OHDA-lesioned animals treated systemically with SKF38393. In one experiment, local infusion of the mGluR5 antagonist MTEP in the DA-denervated rat striatum attenuated the activation of ERK1/2 signaling by SKF38393. In another experiment, 6-OHDA lesions were applied to transgenic mice with a cell-specific knockdown of mGluR5 in D1 receptor-expressing neurons. These mice showed a blunted striatal ERK1/2 activation in response to SFK38393 treatment. Our results reveal that D1-dependent ERK1/2 activation in the DA-denervated striatum depends on a complex interaction between PKA- and Ca2+-dependent signaling pathways that is critically modulated by striatal mGluR5.

Details

ISSN :
15292401 and 02706474
Volume :
34
Database :
OpenAIRE
Journal :
The Journal of Neuroscience
Accession number :
edsair.doi.dedup.....9355f756b13258470d4c744b95d94165