Striatal NurR1 facilitates the dyskinetic state and exacerbates levodopa-induced dyskinesia in a rat model of Parkinson’s disease

Rhyomi C. Sellnow, Kathy Steece-Collier, Feras Altwal, Ivette M. Sandoval, Jeffrey H. Kordower, Timothy J. Collier, Caryl E. Sortwell, Anthony R. West, Fredric P. Manfredsson

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

The transcription factor Nurr1 has been identified to be ectopically induced in the striatum of rodents expressing L-DOPA-induced dyskinesia (LID). In the present study, we sought to characterize Nurr1 as a causative factor in LID expression. We used rAAV2/5 to overexpress Nurr1 or GFP in the parkinsonian striatum of LID-resistant Lewis or LID-prone Fischer-344 (F344) male rats. In a second cohort, rats received the Nurr1 agonist amodiaquine (AQ) together with L-DOPA or ropinirole. All rats received a chronic DA agonist and were evaluated for LID severity. Finally, we performed single-unit recordings and dendritic spine analyses on striatal medium spiny neurons (MSNs) in drug-naïve rAAV-injected male parkinsonian rats. rAAV-GFP injected LID-resistant hemi-parkinsonian Lewis rats displayed mild LID and no induction of striatal Nurr1 despite receiving a high dose of L-DOPA. However, Lewis rats overexpressing Nurr1 developed severe LID. Nurr1 agonism with AQ exacerbated LID in F344 rats. We additionally determined that in L-DOPA-naïve rats striatal rAAV-Nurr1 overexpression (1) increased cortically-evoked firing in a subpopulation of identified striatonigral MSNs, and (2) altered spine density and thin-spine morphology on striatal MSNs; both phenomena mimicking changes seen in dyskinetic rats. Finally, we provide postmortem evidence of Nurr1 expression in striatal neurons of L-DOPA-treated PD patients. Our data demonstrate that ectopic induction of striatal Nurr1 is capable of inducing LID behavior and associated neuropathology, even in resistant subjects. These data support a direct role of Nurr1 in aberrant neuronal plasticity and LID induction, providing a potential novel target for therapeutic development.

Original languageEnglish (US)
Pages (from-to)3675-3691
Number of pages17
JournalJournal of Neuroscience
Volume40
Issue number18
DOIs
StatePublished - Apr 29 2020
Externally publishedYes

Keywords

  • Dopamine
  • Levodopa induced dyskinesia
  • Nurr1
  • Parkinson’s disease
  • Plasticity

ASJC Scopus subject areas

  • Neuroscience(all)

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