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

doi:10.1016/j.xcrm.2024.101566

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

Cell Rep Med. 2024 May 8:101566. doi: 10.1016/j.xcrm.2024.101566. Online ahead of print.

Authors

Cong Shen¹, Bo Shen¹, Dechen Liu², Linlin Han¹, Kexin Zou², Linhua Gan¹, Jingyu Ren², Bin Wu¹, Yilin Tang¹, Jue Zhao¹, Yimin Sun¹, Fengtao Liu¹, Wenbo Yu¹, Haishan Yao³, Jianjun Wu⁴, Jian Wang⁵

Affiliations

¹ Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, China.
² Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
³ Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. Electronic address: haishanyao@ion.ac.cn.
⁴ Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: wujianjun@fudan.edu.cn.
⁵ Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: wangjian_hs@fudan.edu.cn.

PMID: 38759649
DOI: 10.1016/j.xcrm.2024.101566

Abstract

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 (GPe^{TRAPed in LID}) is observed during dyskinesia. Optogenetic inhibition of GPe^{TRAPed in LID} significantly ameliorates LID, whereas reactivation of GPe^{TRAPed in LID} evokes dyskinetic behavior in the levodopa-off state. Simultaneous chemogenetic reactivation of GPe^{TRAPed in LID} and another previously reported ensemble in striatum fully reproduces the dyskinesia induced by high-dose levodopa. Finally, we characterize GPe^{TRAPed 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.

Keywords: Parkinson's disease; activity-dependent tools; globus pallidus external segment; levodopa-induced dyskinesia; optogenetics.