Parkinson’s disease (PD) is a neurodegenerative disorder that arises following the death of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). DAergic signaling from these neurons is required for proper signaling of the basal ganglia, a circuit that regulates habitual motor behaviors. As the SNc degenerates, DA signaling to the hub of the basal ganglia—the striatum—is drastically reduced. This progressive loss results in the development of parkinsonian motor symptoms, including bradykinesia, tremor, and gait problems. To treat these symptoms, the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA) can be administered to reintroduce DA signaling in the striatum. Unfortunately, chronic treatment with L-DOPA inevitably leads to the development of new motor symptoms, called L-DOPA-induced dyskinesia (LID), in the majority of PD patients. LID development is a complex, multifaceted process. The aim of this dissertation is to elucidate the mechanism of LID by studying abnormal presynaptic signaling and the aberrant postsynaptic striatal plasticity induced in dyskinesia. First, we found that DA release from serotonin (5-HT) cells of the dorsal raphe nucleus (DRN) is a critical contributing factor to LID in a rat model of PD, and that regulation of DRN neurons blocks LID development. We showed this by using recombinant adeno-associated virus (rAAV) to express the DA autoreceptor D2Rs in DRN neurons, giving them ability to regulate abnormal DA release. Treatment with rAAV-D2Rs blocks LID development by decreasing DA efflux into the striatum. Second, we have characterized a novel postsynaptic molecular driver of LID, Nurr1. Nurr1 has been identified in genetic screens to be significantly upregulated in dyskinetic animal models. Therapies aimed at increasing Nurr1 are currently being investigated for PD, as the transcription factor is required for the health and long-term maintenance of the DA cells that degenerate in the disease. This dissertation provides evidence that Nurr1 plays a direct role in LID development. Viral expression of Nurr1 in the striatum can induce severe LID in a rat strain that is resistant to LID. Additionally, we showed that LID-associated Nurr1 expression is induced by direct stimulation of the pro-movement pathway of the basal ganglia. Finally, we determined that Nurr1 expression causes changes in both the activity and morphology of striatal medium spiny neurons (MSNs). We have shown that, independent of L-DOPA administration, Nurr1 causes altered striatal activity that mimics activity changes seen in dyskinetic animals. Ectopic Nurr1 expression also causes L-DOPA-independent decreases in dendritic spines. As dendritic spine plasticity is a hallmark of LID, our data suggests that Nurr1 plays a direct role in these maladaptive changes. Together, this dissertation provides compelling evidence for both presynaptic and postsynaptic mechanisms of LID development.
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