Evaluating cell type-specific non-dopaminergics as a Parkinson's treatment paradigm

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Parkinson’s disease (PD) is a debilitating neurodegenerative movement disorder, characterized by loss of dopaminergic cells. Primary treatments have relied on replenishing dopamine (e.g. levodopa), however, over time these drugs lose efficacy and lead to incapacitating levodopa induced dyskinesias (LID). These shortcomings suggest that PD cannot be understood or treated by dopaminergic pathways alone. Among non- dopaminergic mechanisms, synaptic receptors are prime candidates for manipulation, however relevant experiments have thus far not yielded promising results. These interventions have suffered from a lack of cellular specificity—the striatum, robustly implicated in PD, contains distinct cell types with opposing behavioral functionality. The inability to target pharmacological agents to just one of these cell types has produced a major gap in the understanding and treatment of PD. To address this limitation, we recently developed DART (Drugs Acutely Restricted by Tethering), a genetically encoded drug-targeting technology that offers the first opportunity to establish behavioral roles of a specific receptor on a defined cell type. In this proposal we will apply cell type- specific synaptic receptor interventions in PD and LID in mouse models. This work will provide unprecedented circuit and molecular insights into PD and LID pathophysiology. In addition, it may provide a roadmap for cell type-specific restriction as a potentially general paradigm for increasing drug efficacy.