2. Academic Validation
  3. Enhancing striatal acetylcholine facilitates dopamine release and striatal output in parkinsonian mice

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

  • Cell Biosci. 2024 Dec 3;14(1):146. doi: 10.1186/s13578-024-01328-z.
Hongxia Li 1 2,  Ziluo Chen 2,  Yuyan Tan 1,  Huoqing Luo 3,  Chen Lu 3,  Chao Gao 1,  Xin Shen 1,  Fang Cai 3,  Ji Hu # 4,  Shengdi Chen # 5 6
Affiliations

Affiliations

  • 1 Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Lab for Translational Research of Neurodegenerative Diseases, Institute of Immunochemistry, ShanghaiTech University, Shanghai, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. huji@shanghaitech.edu.cn.
  • 5 Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. chensd@rjh.com.cn.
  • 6 Lab for Translational Research of Neurodegenerative Diseases, Institute of Immunochemistry, ShanghaiTech University, Shanghai, China. chensd@rjh.com.cn.
  • # Contributed equally.
PMID: 39627827 DOI: 10.1186/s13578-024-01328-z
Abstract

Background: L-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.

Results: Using 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 γ-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.

Conclusions: Our 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.

Keywords

Acetylcholine; Dopamine; In vivo; Parkinson’s disease; Striatum.

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