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CK2 oppositely modulates L-DOPA-induced dyskinesia via striatal projection neurons expressing D1 or D2 receptors

Cortés, Marisol; Malave, Lauren; Castello, Julia; Flajolet, Marc; Cenci, M. Angela LU ; Friedman, Eitan and Rebholz, Heike (2017) In Journal of Neuroscience 37(49). p.11930-11946
Abstract

We have previously shown that casein kinase 2 (CK2) negatively regulates dopamine D1 and adenosine A2A receptor signaling in the striatum. Ablation of CK2 in D1 receptor-positive striatal neurons caused enhanced locomotion and exploration at baseline, whereas CK2 ablation in D2 receptor-positive neurons caused increased locomotion after treatment with A2A antagonist, caffeine. Because both, D1 and A2A receptors, play major roles in the cellular responses toL-DOPA in the striatum, these findings prompted us to examine the impact of CK2 ablation on the effects ofL-DOPA treatment in the unilateral 6-OHDA lesioned mouse model of Parkinson’s disease. We report here that knock-out of CK2... (More)

We have previously shown that casein kinase 2 (CK2) negatively regulates dopamine D1 and adenosine A2A receptor signaling in the striatum. Ablation of CK2 in D1 receptor-positive striatal neurons caused enhanced locomotion and exploration at baseline, whereas CK2 ablation in D2 receptor-positive neurons caused increased locomotion after treatment with A2A antagonist, caffeine. Because both, D1 and A2A receptors, play major roles in the cellular responses toL-DOPA in the striatum, these findings prompted us to examine the impact of CK2 ablation on the effects ofL-DOPA treatment in the unilateral 6-OHDA lesioned mouse model of Parkinson’s disease. We report here that knock-out of CK2 in striatonigral neurons reduces the severity ofL-DOPA-induced dyskinesia (LID), a finding that correlates with lowered pERK but unchanged pPKA substrate levels in D1 medium spiny neurons as well as in cholinergic interneurons. In contrast, lack of CK2 in striatopallidal neurons enhances LID and ERK phosphorylation. Coadministration of caffeine with a low dose ofL-DOPA reduces dyskinesia in animals with striatopallidal knock-out to wild-type levels, suggesting a dependence on adenosine receptor activity. We also detect reduced Golf levels in the striatonigral but not in the striatopallidal knock-out in response toL-DOPA treatment. Our work shows, in a rodent model of PD, that treatment-induced dyskinesia and striatal ERK activation are bidirectionally modulated by ablating CK2 in D1- or D2-positive projection neurons, in male and female mice. The results reveal that CK2 regulates signaling events critical to LID in each of the two main populations of striatal neurons.

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Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
-DOPA, Adenosine, CK2, Dopamine, Dyskinesia, Signaling
in
Journal of Neuroscience
volume
37
issue
49
pages
17 pages
publisher
Society for Neuroscience
external identifiers
  • scopus:85037615402
  • wos:000418053700013
ISSN
0270-6474
DOI
10.1523/JNEUROSCI.0443-17.2017
language
English
LU publication?
yes
id
06b1712e-906b-400e-9bb9-fb087c935c2b
date added to LUP
2017-12-21 10:45:57
date last changed
2018-01-16 13:28:25
@article{06b1712e-906b-400e-9bb9-fb087c935c2b,
  abstract     = {<p>We have previously shown that casein kinase 2 (CK2) negatively regulates dopamine D1 and adenosine A<sub>2A</sub> receptor signaling in the striatum. Ablation of CK2 in D1 receptor-positive striatal neurons caused enhanced locomotion and exploration at baseline, whereas CK2 ablation in D2 receptor-positive neurons caused increased locomotion after treatment with A<sub>2A</sub> antagonist, caffeine. Because both, D1 and A<sub>2A</sub> receptors, play major roles in the cellular responses to<sub>L</sub>-DOPA in the striatum, these findings prompted us to examine the impact of CK2 ablation on the effects of<sub>L</sub>-DOPA treatment in the unilateral 6-OHDA lesioned mouse model of Parkinson’s disease. We report here that knock-out of CK2 in striatonigral neurons reduces the severity of<sub>L</sub>-DOPA-induced dyskinesia (LID), a finding that correlates with lowered pERK but unchanged pPKA substrate levels in D1 medium spiny neurons as well as in cholinergic interneurons. In contrast, lack of CK2 in striatopallidal neurons enhances LID and ERK phosphorylation. Coadministration of caffeine with a low dose of<sub>L</sub>-DOPA reduces dyskinesia in animals with striatopallidal knock-out to wild-type levels, suggesting a dependence on adenosine receptor activity. We also detect reduced G<sub>olf</sub> levels in the striatonigral but not in the striatopallidal knock-out in response to<sub>L</sub>-DOPA treatment. Our work shows, in a rodent model of PD, that treatment-induced dyskinesia and striatal ERK activation are bidirectionally modulated by ablating CK2 in D1- or D2-positive projection neurons, in male and female mice. The results reveal that CK2 regulates signaling events critical to LID in each of the two main populations of striatal neurons.</p>},
  author       = {Cortés, Marisol and Malave, Lauren and Castello, Julia and Flajolet, Marc and Cenci, M. Angela and Friedman, Eitan and Rebholz, Heike},
  issn         = {0270-6474},
  keyword      = {-DOPA,Adenosine,CK2,Dopamine,Dyskinesia,Signaling},
  language     = {eng},
  month        = {12},
  number       = {49},
  pages        = {11930--11946},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {CK2 oppositely modulates L-DOPA-induced dyskinesia via striatal projection neurons expressing D1 or D2 receptors},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.0443-17.2017},
  volume       = {37},
  year         = {2017},
}