Striatal Nurr1 Facilitates the Dyskinetic State and Exacerbates Levodopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease
Document Type
Article
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. The transcription factor Nurr1 is ectopically induced in striatal neurons of rats exhibiting levodopa-induced dyskinesia [LID; a side-effect to dopamine replacement strategies in Parkinson's disease (PD)]. Here we asked whether Nurr1 is causing LID. Indeed, rAAV-mediated expression of Nurr1 in striatal neurons was sufficient to overcome LID-resistance, and Nurr1 agonism exacerbated LID severity in dyskinetic rats. Moreover, we found that expression of Nurr1 in l-DOPA naïve hemi-parkinsonian rats resulted in the formation of morphologic and electrophysiological signatures of maladaptive neuronal plasticity; a phenomenon associated with LID. Finally, we determined that ectopic Nurr1 expression can be found in the putamen of l-DOPA-treated PD patients. These data suggest that striatal Nurr1 is an important mediator of the formation of LID.
Keywords
Parkinson's disease, dopamine, levodopa induced dyskinesia, nurr1, plasticity
Medical Subject Headings
Aged; Animals; Corpus Striatum (drug effects, metabolism); Dyskinesia, Drug-Induced (metabolism, pathology); Female; Humans; Levodopa (toxicity); Male; Nuclear Receptor Subfamily 4, Group A, Member 2 (biosynthesis); Oxidopamine (toxicity); Parkinsonian Disorders (chemically induced, metabolism, pathology); Rats; Rats, Inbred F344; Rats, Inbred Lew; Rats, Sprague-Dawley
Publication Date
4-29-2020
Publication Title
The Journal of neuroscience : the official journal of the Society for Neuroscience
E-ISSN
1529-2401
Volume
40
Issue
18
First Page
3675
Last Page
3691
PubMed ID
32238479
Digital Object Identifier (DOI)
10.1523/JNEUROSCI.2936-19.2020
Recommended Citation
Sellnow, Rhyomi C.; Steece-Collier, Kathy; Altwal, Feras; Sandoval, Ivette M.; Kordower, Jeffrey H.; Collier, Timothy J.; Sortwell, Caryl E.; West, Anthony R.; and Manfredsson, Fredric P., "Striatal Nurr1 Facilitates the Dyskinetic State and Exacerbates Levodopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease" (2020). Translational Neuroscience. 1452.
https://scholar.barrowneuro.org/neurobiology/1452