Striatal Dopamine Induced ERK Phosphorylation Is Altered in Mouse Models of Monogenic Dystonia

Chiara Melis, Genevieve Beauvais, Brian S. Muntean, Maria Daniela Cirnaru, Garrett Otrimski, Jordi Creus-Muncunill, Kirill A. Martemyanov, Pedro Gonzalez-Alegre, Michelle E. Ehrlich

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Similar to some monogenic forms of dystonia, levodopa-induced dyskinesia is a hyperkinetic movement disorder with abnormal nigrostriatal dopaminergic neurotransmission. Molecularly, it is characterized by hyper-induction of phosphorylation of extracellular signal-related kinase in response to dopamine in medium spiny neurons of the direct pathway. Objectives: The objective of this study was to determine if mouse models of monogenic dystonia exhibit molecular features of levodopa-induced dyskinesia. Methods: Western blotting and quantitative immunofluorescence was used to assay baseline and/or dopamine-induced levels of the phosphorylated kinase in the striatum in mouse models of DYT1, DYT6, and DYT25 expressing a reporter in dopamine D1 receptor-expressing projection neurons. Cyclic adenosine monophosphate (cAMP) immunoassay and adenylyl cyclase activity assays were also performed. Results: In DYT1 and DYT6 models, blocking dopamine reuptake with cocaine leads to enhanced extracellular signal-related kinase phosphorylation in dorsomedial striatal medium spiny neurons in the direct pathway, which is abolished by pretreatment with the N-methyl-d-aspartate antagonist MK-801. Phosphorylation is decreased in a model of DYT25. Levels of basal and stimulated cAMP and adenylyl cyclase activity were normal in the DYT1 and DYT6 mice and decreased in the DYT25 mice. Oxotremorine induced increased abnormal movements in the DYT1 knock-in mice. Conclusions: The increased dopamine induction of extracellular signal-related kinase phosphorylation in 2 genetic types of dystonia, similar to what occurs in levodopa-induced dyskinesia, and its decrease in a third, suggests that abnormal signal transduction in response to dopamine in the postsynaptic nigrostriatal pathway might be a point of convergence for dystonia and other hyperkinetic movement disorders, potentially offering common therapeutic targets.

Original languageEnglish (US)
JournalMovement Disorders
DOIs
StateAccepted/In press - 2021
Externally publishedYes

Keywords

  • ERK
  • dopamine
  • dystonia
  • levodopa-induced dyskinesia
  • map kinase
  • striatum

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Fingerprint Dive into the research topics of 'Striatal Dopamine Induced ERK Phosphorylation Is Altered in Mouse Models of Monogenic Dystonia'. Together they form a unique fingerprint.

Cite this