Striatal Microcircuit Mechanisms of Tardive Dyskinesia

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Project Summary/Abstract Long-term treatment with dopamine D2/D3 receptor antagonists (neuroleptics) often causes involuntary orofacial movements (lip smacking, tongue protrusion), termed tardive dyskinesia (TD). Once established, TD is often irreversible. Given the crucial role these medications play in the treatment of psychiatric disease, as well as their common usage in gastrointestinal disorders, migraine, and other conditions, TD is unfortunately quite common. However, we know very little about the physiological underpinnings of its induction or expression. Longstanding theories focus on D2 receptor blockade and upregulation, but many tools used to develop these theories cannot distinguish between D2 and D3 receptors, nor the role of receptors expressed in multiple cell types. For this reason, it is unclear which dopamine receptors are critical to the induction of TD. In addition, existing studies implicate dopamine signaling in both acute and chronic responses to neuroleptics, but few if any studies have measured dopamine release or the physiological activity of its striatal targets in freely moving animals experiencing TD. To address some of these gaps in our understanding of TD, the proposed project will use an established mouse model of TD, based on chronic administration of haloperidol, in conjunction with cell type-specific genetic and physiological tools. First, we will test the necessity for D2 or D3 receptors in the induction and expression of TD, through targeted deletion in specific cell types. Second, we will test the role of striatal dopamine release in the induction and expression of TD in freely moving mice, monitoring dopamine with the fluorescent dopamine sensor, dLight and manipulating dopamine with chemogenetics. Third, we will test the role of striatal projection neurons in TD by monitoring or manipulating neural activity with cell type-specific electrophysiology and photometry, or optogenetics. In these latter components, we will use a head-mounted selfie-cam and automated behavior detection to identify individual dyskinetic mouth movements at high temporal resolution. This last innovation will permit alignment of dyskinetic movements to striatal dopamine release and neural activity. Through these efforts, we hope to test longstanding hypotheses regarding the origins of TD, but moreover to identify the physiological correlates of individual dyskinetic movements. We hope these findings will point to new areas for therapeutic development, but also deepen our understanding of how striatal microcircuit function contributes to the control of voluntary (versus involuntary) movement.