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Spontaneous graft-induced dyskinesias are independent of 5-HT neurons and levodopa priming in a model of Parkinson's disease

Lane, Emma L. ORCID:, Harrison, David J., Ramos-Varas, Elena, Hills, Rachel, Turner, Sophie and Lelos, Mariah J. ORCID: 2022. Spontaneous graft-induced dyskinesias are independent of 5-HT neurons and levodopa priming in a model of Parkinson's disease. Movement Disorders 37 (3) , pp. 613-619. 10.1002/mds.28856

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Background The risk of graft-induced dyskinesias (GIDs) presents a major challenge in progressing cell transplantation as a therapy for Parkinson's disease. Current theories implicate the presence of grafted serotonin neurons, hotspots of dopamine release, neuroinflammation and established levodopa-induced dyskinesia. Objective To elucidate the mechanisms of GIDs. Methods Neonatally desensitized, dopamine denervated rats received intrastriatal grafts of human embryonic stem cells (hESCs) differentiated into either ventral midbrain dopaminergic progenitor (vmDA) (n = 15) or ventral forebrain cells (n = 14). Results Of the eight rats with surviving grafts, two vmDA rats developed chronic spontaneous GIDs, which were observed at 30 weeks post-transplantation. GIDs were inhibited by D2-like receptor antagonists and not affected by 5-HT1A/1B/5-HT6 agonists/antagonists. Grafts in GID rats showed more microglial activation and lacked serotonin neurons. Conclusions These findings argue against current thinking that rats do not develop spontaneous GID and that serotonin neurons are causative, rather indicating that GID can be induced in rats by hESC-derived dopamine grafts and, critically, can occur independently of both previous levodopa exposure and grafted serotonin neurons.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Additional Information: This is an open access article under the terms of the Creative Commons Attribution License
Publisher: Wiley
ISSN: 0885-3185
Funders: MRC, Parkinson's UK
Date of First Compliant Deposit: 12 November 2021
Date of Acceptance: 20 October 2021
Last Modified: 05 Jan 2024 02:26

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