# Striatal Mechanisms of Levodopa-Induced Dyskinesia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $282,625

## Abstract

Project Summary
Levodopa-induced dyskinesia (LID) commonly develops during long-term treatment of Parkinson's Disease,
affecting most patients after 5-10 years of treatment. The abnormal involuntary movements eventually limit the
levodopa dose, and often patients require deep brain stimulation (DBS). The neural mechanisms of LID are not
fully understood, but the leading hypothesis is that levodopa triggers aberrant activity in the input nucleus of
the basal ganglia, the striatum. Even in the advanced stages of disease, however, levodopa continues to have
both therapeutic and pathological effects, promoting normal movement and abnormal involuntary movements.
This clinical observation led us to hypothesize that within the striatum, distinct populations of neurons correlate
with dyskinetic versus prokinetic (therapeutic) effects of levodopa. Our pilot studies indicate that a substantial
fraction of striatal neurons show strong correlations in their activity with either increased normal movement, or
dyskinesia, and few neurons correlate with both responses. By understanding the intrinsic and synaptic
properties that distinguish these two groups of striatal neurons, subsequent drug development might be able to
selectively target movement neurons, relieving motor symptoms of Parkinson's Disease, without affecting
dyskinetic neurons and avoiding dyskinesia. Using a combination of awake-behaving single-unit recordings,
optogenetics, and ex vivo slice recordings in a mouse model of LID, this proposal aims to (1) characterize
striatal direct pathway neuronal responses to levodopa, including identifying units whose firing correlates with
dyskinesia, (2) determine whether these neurons cause dyskinesia, and (3) identify the underlying cellular
mechanisms (alterations in intrinsic excitability and/or excitatory inputs) that distinguish them. To test the
causal role of dyskinesia-correlated striatal units in dyskinesia, we will use the novel transgenic tool, Targeted
Recombination in Active Populations (TRAP), which allows capture and subsequent manipulation of previously
activated neurons. These studies will provide the first detailed look at whether levodopa triggers therapeutic
and dyskinetic effects through two different striatal effector populations, and begin to dissect the underlying
cellular and synaptic mechanisms.
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## Key facts

- **NIH application ID:** 10181085
- **Project number:** 5R01NS101354-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Alexandra Nelson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $282,625
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10181085

## Citation

> US National Institutes of Health, RePORTER application 10181085, Striatal Mechanisms of Levodopa-Induced Dyskinesia (5R01NS101354-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10181085. Licensed CC0.

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