Advanced

L-DOPA activates ERK signaling and phosphorylates histone H3 in the striatonigral medium spiny neurons of hemiparkinsonian mice

Santini, Emanuela; Alcacer, Cristina LU ; Cacciatore, Silvia; Heiman, Myriam; Hervé, Denis; Greengard, Paul; Girault, Jean-Antoine; Valjent, Emmanuel and Fisone, Gilberto (2009) In Journal of Neurochemistry 108(3). p.621-633
Abstract

In the dopamine-depleted striatum, extracellular signal-regulated kinase (ERK) signaling is implicated in the development of l-DOPA-induced dyskinesia. To gain insights on its role in this disorder, we examined the effects of l-DOPA on the state of phosphorylation of ERK and downstream target proteins in striatopallidal and striatonigral medium spiny neurons (MSNs). For this purpose, we employed mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoters for the dopamine D2 receptor (Drd2-EGFP mice) or the dopamine D1 receptor (Drd1a-EGFP mice), which are expressed in striatopallidal and striatonigral MSNs, respectively. In 6-hydroxydopamine-lesioned Drd2-EGFP mice, l-DOPA increased... (More)

In the dopamine-depleted striatum, extracellular signal-regulated kinase (ERK) signaling is implicated in the development of l-DOPA-induced dyskinesia. To gain insights on its role in this disorder, we examined the effects of l-DOPA on the state of phosphorylation of ERK and downstream target proteins in striatopallidal and striatonigral medium spiny neurons (MSNs). For this purpose, we employed mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoters for the dopamine D2 receptor (Drd2-EGFP mice) or the dopamine D1 receptor (Drd1a-EGFP mice), which are expressed in striatopallidal and striatonigral MSNs, respectively. In 6-hydroxydopamine-lesioned Drd2-EGFP mice, l-DOPA increased the phosphorylation of ERK, mitogen- and stress-activated kinase 1 and histone H3, selectively in EGFP-negative MSNs. Conversely, a complete co-localization between EGFP and these phosphoproteins was observed in Drd1a-EGFP mice. The effect of l-DOPA was prevented by blockade of dopamine D1 receptors. The same pattern of activation of ERK signaling was observed in dyskinetic mice, after repeated administration of l-DOPA. Our results demonstrate that in the dopamine-depleted striatum, l-DOPA activates ERK signaling specifically in striatonigral MSNs. This regulation may result in ERK-dependent changes in striatal plasticity leading to dyskinesia.

(Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
keywords
Bacterial artificial chromosome, L-DOPA-induced dyskinesia, Mitogen- and stress-activated kinase 1, Parkinson's disease, Striatum, Transgenic mice
in
Journal of Neurochemistry
volume
108
issue
3
pages
13 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:58149333252
ISSN
0022-3042
DOI
10.1111/j.1471-4159.2008.05831.x
language
English
LU publication?
no
id
9f296b0d-8bd4-4d98-a5bb-83869cb2765a
date added to LUP
2017-02-14 16:29:36
date last changed
2017-10-22 05:26:28
@article{9f296b0d-8bd4-4d98-a5bb-83869cb2765a,
  abstract     = {<p>In the dopamine-depleted striatum, extracellular signal-regulated kinase (ERK) signaling is implicated in the development of l-DOPA-induced dyskinesia. To gain insights on its role in this disorder, we examined the effects of l-DOPA on the state of phosphorylation of ERK and downstream target proteins in striatopallidal and striatonigral medium spiny neurons (MSNs). For this purpose, we employed mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoters for the dopamine D<sub>2</sub> receptor (Drd2-EGFP mice) or the dopamine D<sub>1</sub> receptor (Drd1a-EGFP mice), which are expressed in striatopallidal and striatonigral MSNs, respectively. In 6-hydroxydopamine-lesioned Drd2-EGFP mice, l-DOPA increased the phosphorylation of ERK, mitogen- and stress-activated kinase 1 and histone H3, selectively in EGFP-negative MSNs. Conversely, a complete co-localization between EGFP and these phosphoproteins was observed in Drd1a-EGFP mice. The effect of l-DOPA was prevented by blockade of dopamine D<sub>1</sub> receptors. The same pattern of activation of ERK signaling was observed in dyskinetic mice, after repeated administration of l-DOPA. Our results demonstrate that in the dopamine-depleted striatum, l-DOPA activates ERK signaling specifically in striatonigral MSNs. This regulation may result in ERK-dependent changes in striatal plasticity leading to dyskinesia.</p>},
  author       = {Santini, Emanuela and Alcacer, Cristina and Cacciatore, Silvia and Heiman, Myriam and Hervé, Denis and Greengard, Paul and Girault, Jean-Antoine and Valjent, Emmanuel and Fisone, Gilberto},
  issn         = {0022-3042},
  keyword      = {Bacterial artificial chromosome,L-DOPA-induced dyskinesia,Mitogen- and stress-activated kinase 1,Parkinson's disease,Striatum,Transgenic mice},
  language     = {eng},
  number       = {3},
  pages        = {621--633},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Neurochemistry},
  title        = {L-DOPA activates ERK signaling and phosphorylates histone H3 in the striatonigral medium spiny neurons of hemiparkinsonian mice},
  url          = {http://dx.doi.org/10.1111/j.1471-4159.2008.05831.x},
  volume       = {108},
  year         = {2009},
}