Enhancing striatal acetylcholine facilitates dopamine release and striatal output in parkinsonian mice

doi:10.1186/s13578-024-01328-z

	Enhancing striatal acetylcholine facilitates dopamine release and striatal output in parkinsonian mice
	Li, Hongxia1,2,3 ; Chen, Ziluo3 ; Tan, Yuyan 1,2; Luo, Huoqing4 ; Lu, Chen4 ; Gao, Chao 1,2; Shen, Xin 1,2; Cai, Fang4 ; Hu, Ji4 ; Chen, Shengdi1,2,3
	2024-12-03
发表期刊	CELL AND BIOSCIENCE (IF:6.1[JCR-2023],7.0[5-Year])
EISSN	2045-3701
卷号	14 期号:1
发表状态	已发表
DOI	10.1186/s13578-024-01328-z
摘要	BackgroundL-DOPA has been considered the first-line therapy for treating Parkinson's disease (PD) via restoring striatal dopamine (DA) to normalize the activity of local spiny projection neurons (SPNs) in the direct (dSPNs) pathway and the indirect (iSPNs) pathway. While the changes in striatal acetylcholine (ACh) induced by increasing DA have been extensively discussed, their validity remains controversial. Inhibition of striatal cholinergic signaling attenuates PD motor deficits. Interestingly, enhancing striatal ACh triggers local DA release, suggesting the pro-kinetic effects of ACh in movement control. Here, we investigated the in-vivo dynamics of ACh in the dorsolateral striatum (DLS) of the 6-OHDA-lesioned mouse model after L-DOPA administration, as well as its underlying mechanism, and to explore its modulatory role and mechanism in parkinsonian symptoms.ResultsUsing in vivo fiber photometry recordings with genetically encoded fluorescent DA or ACh indicator, we found L-DOPA selectively decreased DLS ACh levels in parkinsonian conditions. DA inhibited ACh release via dopamine D2 receptors and dSPNs-mediated activation of type-A gamma-aminobutyric acid receptors on cholinergic interneurons. Restoring DLS ACh levels during L-DOPA treatment induced additional DA release by activating nicotinic acetylcholine receptors, thereby promoting the activity of dSPNs and iSPNs. Enhancing DLS ACh facilitated L-DOPA-induced turning behavior but not dyskinesia in parkinsonian mice.ConclusionsOur results demonstrated that enhancing striatal ACh facilitated the effect of L-DOPA by modulating DA tone. It may challenge the classical hypothesis of a purely competitive interaction between dopaminergic and cholinergic neuromodulation in improving PD motor deficits. Modulating ACh levels within the dopaminergic system may improve striatal DA availability in PD patients.
关键词	Acetylcholine Dopamine Striatum Parkinson's disease In vivo
URL	查看原文
收录类别	SCI
语种	英语
WOS研究方向	Biochemistry & Molecular Biology
WOS类目	Biochemistry & Molecular Biology
WOS记录号	WOS:001369350700001
出版者	BMC
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/458301
专题	生命科学与技术学院生命科学与技术学院_PI研究组_胡霁组生命科学与技术学院_硕士生信息科学与技术学院_硕士生免疫化学研究所_特聘教授组_陈生弟组
通讯作者	Hu, Ji; Chen, Shengdi
作者单位	1.Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Neurol, Sch Med, Shanghai, Peoples R China 2.Shanghai Jiao Tong Univ, Ruijin Hosp, Inst Neurol, Sch Med, Shanghai, Peoples R China 3.ShanghaiTech Univ, Inst Immunochem, Lab Translat Res Neurodegenerat Dis, Shanghai, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
第一作者单位	上海科技大学
通讯作者单位	生命科学与技术学院; 上海科技大学
推荐引用方式 GB/T 7714	Li, Hongxia,Chen, Ziluo,Tan, Yuyan,et al. Enhancing striatal acetylcholine facilitates dopamine release and striatal output in parkinsonian mice[J]. CELL AND BIOSCIENCE,2024,14(1).
APA	Li, Hongxia.,Chen, Ziluo.,Tan, Yuyan.,Luo, Huoqing.,Lu, Chen.,...&Chen, Shengdi.(2024).Enhancing striatal acetylcholine facilitates dopamine release and striatal output in parkinsonian mice.CELL AND BIOSCIENCE,14(1).
MLA	Li, Hongxia,et al."Enhancing striatal acetylcholine facilitates dopamine release and striatal output in parkinsonian mice".CELL AND BIOSCIENCE 14.1(2024).