Striatal Nurr1 Facilitates the Dyskinetic State and Exacerbates Levodopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease.

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 (MSN) in drug-naive 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 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-naive rats striatal rAAV-Nurr1 overexpression 1) increased cortically-evoked firing in a sub-population of identified striatonigral MSNs, and 2) altering spine density and thin-spine morphology on striatal MSN; both phenomena mimicking changes seen in dyskinetic rats. Finally, we provide post-mortem 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. Significance Statement 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 naive hemiparkinsonian rats resulted in the formation of morphological 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 Parkinson’s disease patients. These data suggest that striatal Nurr1 is an important mediator of the formation of LID.