Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson's Model
Document Type
Article
Abstract
Previous work revealed an inverse correlation between tobacco smoking and Parkinson's disease (PD) that is associated with nicotine-induced neuroprotection of dopaminergic (DA) neurons against nigrostriatal damage in PD primates and rodent models. Nicotine, a neuroactive component of tobacco, can directly alter the activity of midbrain DA neurons and induce non-DA neurons in the substantia nigra (SN) to acquire a DA phenotype. Here, we investigated the recruitment mechanism of nigrostriatal GABAergic neurons to express DA phenotypes, such as transcription factor Nurr1 and DA-synthesizing enzyme tyrosine hydroxylase (TH), and the concomitant effects on motor function. Wild-type and α-syn-overexpressing (PD) mice treated with chronic nicotine were assessed by behavioral pattern monitor (BPM) and immunohistochemistry/in situ hybridization to measure behavior and the translational/transcriptional regulation of neurotransmitter phenotype following selective Nurr1 overexpression or DREADD-mediated chemogenetic activation. We found that nicotine treatment led to a transcriptional TH and translational Nurr1 upregulation within a pool of SN GABAergic neurons in wild-type animals. In PD mice, nicotine increased Nurr1 expression, reduced the number of α-syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicit de novo translational upregulation of Nurr1. Retrograde labeling revealed that a fraction of these GABAergic neurons projects to the dorsal striatum. Finally, concomitant depolarization and Nurr1 overexpression within GABA neurons were sufficient to mimic nicotine-mediated dopamine plasticity. Revealing the mechanism of nicotine-induced DA plasticity protecting SN neurons against nigrostriatal damage could contribute to developing new strategies for neurotransmitter replacement in PD.
Keywords
alpha-synuclein, dopamine, neurotransmitter-switching, nicotine, substantia nigra, tyrosine-hydroxylase
Medical Subject Headings
Mice; Animals; alpha-Synuclein (metabolism); Parkinson Disease (metabolism); Dopamine (metabolism); Nicotine (pharmacology); Substantia Nigra (metabolism); Dopaminergic Neurons (metabolism); GABAergic Neurons (metabolism); Phenotype
Publication Date
2-20-2023
Publication Title
International journal of molecular sciences
E-ISSN
1422-0067
Volume
24
Issue
4
PubMed ID
36835612
Digital Object Identifier (DOI)
10.3390/ijms24044204
Recommended Citation
Lai, Jessica IChi; Porcu, Alessandra; Romoli, Benedetto; Keisler, Maria; Manfredsson, Fredric P.; Powell, Susan B.; and Dulcis, Davide, "Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson's Model" (2023). Translational Neuroscience. 2273.
https://scholar.barrowneuro.org/neurobiology/2273