Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson’s Model
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 di...
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| Format: | Article |
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/4204 |
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| author | Jessica IChi Lai Alessandra Porcu Benedetto Romoli Maria Keisler Fredric P. Manfredsson Susan B. Powell Davide Dulcis |
| author_facet | Jessica IChi Lai Alessandra Porcu Benedetto Romoli Maria Keisler Fredric P. Manfredsson Susan B. Powell Davide Dulcis |
| author_sort | Jessica IChi Lai |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T08:41:28Z |
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| id | doaj.art-f7a2d58111d94bf4985cbef23f50f6d2 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:41:28Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f7a2d58111d94bf4985cbef23f50f6d22023-11-16T21:10:58ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244420410.3390/ijms24044204Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson’s ModelJessica IChi Lai0Alessandra Porcu1Benedetto Romoli2Maria Keisler3Fredric P. Manfredsson4Susan B. Powell5Davide Dulcis6Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USADepartment of Psychiatry, University of California San Diego, La Jolla, CA 92093, USADepartment of Psychiatry, University of California San Diego, La Jolla, CA 92093, USADepartment of Psychiatry, University of California San Diego, La Jolla, CA 92093, USADepartment of Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USADepartment of Psychiatry, University of California San Diego, La Jolla, CA 92093, USADepartment of Psychiatry, University of California San Diego, La Jolla, CA 92093, USAPrevious 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.https://www.mdpi.com/1422-0067/24/4/4204nicotinedopaminetyrosine-hydroxylasealpha-synucleinneurotransmitter-switchingsubstantia nigra |
| spellingShingle | Jessica IChi Lai Alessandra Porcu Benedetto Romoli Maria Keisler Fredric P. Manfredsson Susan B. Powell Davide Dulcis Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson’s Model International Journal of Molecular Sciences nicotine dopamine tyrosine-hydroxylase alpha-synuclein neurotransmitter-switching substantia nigra |
| title | Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson’s Model |
| title_full | Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson’s Model |
| title_fullStr | Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson’s Model |
| title_full_unstemmed | Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson’s Model |
| title_short | Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson’s Model |
| title_sort | nicotine mediated recruitment of gabaergic neurons to a dopaminergic phenotype attenuates motor deficits in an alpha synuclein parkinson s model |
| topic | nicotine dopamine tyrosine-hydroxylase alpha-synuclein neurotransmitter-switching substantia nigra |
| url | https://www.mdpi.com/1422-0067/24/4/4204 |
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