A major limitation in treating Parkinson's disease (PD) is the development of L-Dopa induced dyskinesias (LIDs). LIDs are disruptive involuntary movements that lead to a decreased quality of life in PD patients. To date, the neural mechanism underlying this debilitating side effect is poorly understood. Thus, this proposal combines neurophysiology, optogenetics, and automated motion tracking to explore the mechanism involved. Prior work demonstrates a reduction in LIDs following serotonergic neuron ablation in a rat model of PD. In the proposed study, we will address the involvement of the serotonergic system by first determining if serotonergic neurons are necessary for the development of LIDs (Aim 1) and then determining if it is specifically serotonergic projections to D1 neurons in the striatum that modulate LIDs (Aim 2). To identify the general role of serotonergic system in the development of LIDs, we will inject hemiparkinsonian Lmx1bf/f/p mice, lacking serotonergic neurons in the central nervous system, with L-dopa and document abnormal involuntary movements. Next, we propose to optogenetically target the dorsal raphe nucleus (DRN) as the main nucleus involved in LIDs, as it heavily projects to the striatum. To study the interaction between the serotonergic and dopaminergic systems in the striatum during LIDs, we first combine striatal neuronal ensemble recordings with pharmacological manipulations. Striatal activity (neuronal firing rate and local field potential) will be paired wih LIDs in awake-behaving animals. Secondly, we measure LIDs while pharmacologically inhibiting serotonergic neurons and transiently stimulating D1 neurons with optogenetics techniques. Elucidating the mechanism of LIDs may lead to the development of therapies that will inhibit dyskinesias, enhance motor benefits from L-dopa, and potentially avoid the need for more invasive surgical treatment, significantly increasing the quality of life in these patients.

Public Health Relevance

L-dopa induced dyskinesias are a debilitating side effect of long-term treatment of Parkinson's disease with the dopamine precursor, L-dopa. Here, we propose to study the mechanism through which these dyskinesias develop in a Parkinson's disease mouse model. By concentrating on the possible interaction between the serotonergic and dopaminergic systems we hope to elucidate the mechanism responsible for L- dopa induced dyskinesias to provide new targets in Parkinson's disease treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS092190-02
Application #
9135143
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sieber, Beth-Anne
Project Start
2015-07-01
Project End
2018-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Iowa
Department
Neurology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52246
Alberico, Stephanie L; Kim, Young-Cho; Lence, Tomas et al. (2017) Axial levodopa-induced dyskinesias and neuronal activity in the dorsal striatum. Neuroscience 343:240-249