Striatal Mechanisms of Dyskinesia and Impulse Control in Parkinson’s Disease

Project Abstract The motor symptoms of Parkinson’s Disease (PD) are frequently treated with dopamine replacement therapies, such as the dopamine precursor levodopa or dopamine receptor agonists. While very effective for some of the cardinal motor features, these medications can cause two major complications: levodopa-induced dyskinesia (LID) and impulse control disorder (ICD). LID consists of drug-induced abnormal involuntary movements, and is closely associated with levodopa. ICD manifests as a syndrome of impulsive and/or compulsive behaviors, such as pathological gambling, hypersexuality, or binge eating, and is closely associated with dopamine D2/3R agonists. Little is known about the synaptic or circuit mechanisms of either disorder, though substantial progress has been made on LID through the use of animal models of PD/LID. In our prior work, we have found that a subset of striatal direct pathway medium spiny neurons achieve high levodopa-evoked firing rates in vivo, which correlate with and cause dyskinesia in the mouse model. Other intermingled direct pathway neurons correlate with the therapeutic effects of levodopa. We have also recently developed a mouse model of PD/ICD, based on a delay discounting task and administration of the dopamine agonist pramipexole, which will permit more mechanistic studies. In this proposal we will explore some cellular and circuit mechanisms of LID and ICD, using in vivo and ex vivo electrophysiology, optogenetics, and chemogenetics in mouse models. This proposal aims to (1) test whether local striatal inhibitory synapses are altered in and contribute to LID, (2) determine whether extrinsic inhibitory synapses from the globus pallidus to the striatum are altered in and contribute to LID, and (3) begin to explore the striatal mechanisms of ICD. These studies will build on our prior work in LID to unravel its cellular mechanisms, but also determine if ICD is mediated by similar or distinct processes. Together, these studies will lay the groundwork for new PD treatments that harness the benefits of dopamine without the complications.