Bidirectional regulation of levodopa-induced dyskinesia by a specific neural ensemble in globus pallidus external segment.

Cong Shen, Bo Shen, Dechen Liu, Linlin Han, Kexin Zou, Linhua Gan, Jingyu Ren, Bin Wu, Yilin Tang, Jue Zhao, Yimin Sun, Fengtao Liu, Wenbo Yu, Haishan Yao, Jianjun Wu, Jian Wang

Cell reports. Medicine 2024 Jun 18

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Levodopa-induced dyskinesia (LID) is an intractable motor complication arising in Parkinson's disease with the progression of disease and chronic treatment of levodopa. However, the specific cell assemblies mediating dyskinesia have not been fully elucidated. Here, we utilize the activity-dependent tool to identify three brain regions (globus pallidus external segment [GPe], parafascicular thalamic nucleus, and subthalamic nucleus) that specifically contain dyskinesia-activated ensembles. An intensity-dependent hyperactivity in the dyskinesia-activated subpopulation in GPe (GPeTRAPed in LID) is observed during dyskinesia. Optogenetic inhibition of GPeTRAPed in LID significantly ameliorates LID, whereas reactivation of GPeTRAPed in LID evokes dyskinetic behavior in the levodopa-off state. Simultaneous chemogenetic reactivation of GPeTRAPed in LID and another previously reported ensemble in striatum fully reproduces the dyskinesia induced by high-dose levodopa. Finally, we characterize GPeTRAPed in LID as a subset of prototypic neurons in GPe. These findings provide theoretical foundations for precision medication and modulation of LID in the future. Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Cong Shen, Bo Shen, Dechen Liu, Linlin Han, Kexin Zou, Linhua Gan, Jingyu Ren, Bin Wu, Yilin Tang, Jue Zhao, Yimin Sun, Fengtao Liu, Wenbo Yu, Haishan Yao, Jianjun Wu, Jian Wang. Bidirectional regulation of levodopa-induced dyskinesia by a specific neural ensemble in globus pallidus external segment. Cell reports. Medicine. 2024 Jun 18;5(6):101566