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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Marisol Cortés
  • Lauren Malave
  • Julia Castello
  • Marc Flajolet
  • M. Angela Cenci
  • Eitan Friedman
  • Heike Rebholz
Organisations
External organisations
  • City University of New York
  • Rockefeller University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences

Keywords

  • -DOPA, Adenosine, CK2, Dopamine, Dyskinesia, Signaling
Original languageEnglish
Pages (from-to)11930-11946
Number of pages17
JournalJournal of Neuroscience
Volume37
Issue number49
Publication statusPublished - 2017 Dec 6
Publication categoryResearch
Peer-reviewedYes