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Reversal of Pathological Motor Behavior in a Model of Parkinson’s Disease by Striatal Dopamine Uncaging

Miguel A. Zamora-Ursulo, Job Perez-Becerra, Luis A. Tellez, Nadia Saderi, Luis Carrillo-Reid

Abstract

Motor deficits observed in Parkinson’s disease (PD) are caused by the loss of dopaminergic neurons and the subsequent dopamine depletion in different brain areas. The most common therapy to treat motor symptoms for patients with this disorder is the systemic intake of L-DOPA that increases dopamine levels in all the brain, making it difficult to discern the main locus of dopaminergic action in the alleviation of motor control. Caged compounds are molecules with the ability to release neuromodulators locally in temporary controlled conditions using light. In the present study, we measured the turning behavior of unilateral dopamine-depleted mice before and after dopamine uncaging.

Introduction

Parkinson’s disease (PD) is a devastating neurodegenerative disorder caused by the progressive loss of dopamine in the brain [1]. PD is characterized by motor abnormalities such as bradykinesia, tremor, and posture unbalance [2–4]. Motor dysfunctions in PD emerge after the severe destruction of dopaminergic neurons of the mesencephalon and the degeneration of their axonal projections to the striatum [5, 6]. The striatum is the main entry gateway of the basal ganglia, and it has been shown that the loss of dopamine evokes abnormal synchronization of striatal neuronal populations [7–11].

Materials and method

Experiments were performed on C57BL/6J male mice, 60–70 postnatal days before surgical procedures. We used 75 mice for experiments and data analyses and discarded 12 animals due to failures in stereotaxic coordinates to reach the SNc. Mice were housed on a 12 h light-dark cycle with food and water ad libitum. All experimental procedures were carried out in accordance with the guidelines of the Bioethics Committee of the Neurobiology Institute for the care and use of laboratory animals that comply with the standards outlined by the Guide for the Care and Use of Laboratory Animals (NIH).

Results

To characterize the turning behavior described in unilateral dopamine-depleted mice, we injected 6-OHDA into the right SNc on one group of mice (dopamine-depleted), or saline solution in another group of mice (control) (Fig 1A). After 3 weeks of 6-OHDA injection in the SNc, we observed a decrease of the dopaminergic innervation to the striatum of the lesioned side of the brain (Fig 1B) corresponding to ~80% loss of the dopaminergic terminals (Fig 1C; normalized TH fluorescence of lesioned side: 19.74% ± 4.135%).

Discussion

We demonstrated that light-controlled dopamine release in the striatum of unilateral dopamine-depleted mice evokes contralateral turning behavior that was gradually reduced and disappeared after 60 minutes. Importantly, contralateral turning behavior can be tuned by changing the light power and frequency. The motor outcome caused by striatal dopamine uncaging resembles the effect induced by a low concentration of L-DOPA injected systemically but with better temporal control. Furthermore, striatal LFP recordings showed that dopamine uncaging reduced the pathological neuronal synchronization that has been reported in unilateral dopamine-depleted mice.

Acknowledgments

We thank Vladimir Calderon, Elsa Nydia Hernández Rios, Ericka A. de los Rios Arellano, Martín Garcia Servin, Alejandra Castilla Leon and Deysi Gasca Martinez for technical assistance. We thank Rafa Yuste for the generous donation of materials and reagents.

Citation: Zamora-Ursulo MA, Perez-Becerra J, Tellez LA, Saderi N, Carrillo-Reid L (2023) Reversal of pathological motor behavior in a model of Parkinson’s disease by striatal dopamine uncaging. PLoS ONE 18(8): e0290317. https://doi.org/10.1371/journal.pone.0290317

Editor: Luca Aquili, Murdoch University, AUSTRALIA

Received: May 16, 2023; Accepted: August 6, 2023; Published: August 18, 2023

Copyright: © 2023 Zamora-Ursulo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting information files.

Funding: This research was supported by grants from CONACYT (CF6653, CF154039) and UNAM-DGAPA-PAPIIT (IA201421, IA201819, IN213923) to L.C-R. MA.Z-U. participated in this work in partial fulfillment of the requirements for the Ph.D. degree in Basic Biomedical Sciences at the Universidad Autonoma de San Luis Potosi graduate scholarship from CONACYT (770504). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: NO authors have competing interests.

 

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0290317#ack

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