Astrocytes mediate the dopaminergic modulation of tonic GABAergic signaling in substantia nigra

Astrocytes mediate the dopaminergic modulation of tonic GABAergic signaling in substantia nigra | bioRxiv Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results Astrocytes mediate the dopaminergic modulation of tonic GABAergic signaling in substantia nigra View ORCID Profile DeNard V Simmons , Oscar Andrés Moreno-Ramos , Divya D.A. Raj , View ORCID Profile Konstantin Kaganovsky , View ORCID Profile Arin Pamukcu , View ORCID Profile Nora Vrieler , View ORCID Profile Tatiana Tkatch , Zhong Xie , Ana Isabel Silva de Sousa , View ORCID Profile Enrico Zampese , View ORCID Profile Jun Ding , View ORCID Profile Rajeshwar Awatramani , Charles J. Wilson , View ORCID Profile D. James Surmeier doi: https://doi.org/10.1101/2024.03.27.586699 DeNard V Simmons 1 Department of Neuroscience, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, USA 5 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for DeNard V Simmons Oscar Andrés Moreno-Ramos 2 Department of Neurology, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, USA 5 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Divya D.A. Raj 2 Department of Neurology, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, USA 5 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Konstantin Kaganovsky 3 Department of Neurosurgery, Stanford University School of Medicine , Stanford, CA 94305 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Konstantin Kaganovsky Arin Pamukcu 1 Department of Neuroscience, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, USA 5 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Arin Pamukcu Nora Vrieler 1 Department of Neuroscience, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, USA 5 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nora Vrieler Tatiana Tkatch 1 Department of Neuroscience, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, USA 5 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Tatiana Tkatch Zhong Xie 1 Department of Neuroscience, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, USA 5 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ana Isabel Silva de Sousa 1 Department of Neuroscience, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, USA 5 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Enrico Zampese 1 Department of Neuroscience, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, USA 5 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Enrico Zampese Jun Ding 3 Department of Neurosurgery, Stanford University School of Medicine , Stanford, CA 94305 5 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jun Ding Rajeshwar Awatramani 2 Department of Neurology, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, USA 5 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Rajeshwar Awatramani Charles J. Wilson 4 Department of Neuroscience , Developmental and Regenerative Biology, University of Texas at San Antonio , San Antonio, Texas 78249 Find this author on Google Scholar Find this author on PubMed Search for this author on this site D. James Surmeier 1 Department of Neuroscience, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, USA 5 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for D. James Surmeier For correspondence: j-surmeier{at}northwestern.edu Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Recent studies have implicated dopaminergic signaling within the substantia nigra pars reticulata (SNr) in the emergence of Parkinsonian motor deficits. To better understand the mechanisms underlying this dependence, the ability of dopamine to modulate SNr neuron activity was studied in ex vivo mouse brain slices. In addition to presynaptically inhibiting phasic GABA release, D2 dopamine receptor (D2R) signaling unexpectedly suppressed a tonic, GABA A receptor-mediated inhibition of SNr neuron spiking. Our studies demonstrated that this tonic modulation was largely mediated by GAT-1-dependent GABA release from ALDH1A1-expressing dopaminergic neurons. In contrast, the ability of D2R agonists to disinhibit SNr neurons depended upon D2R-expressing astrocytes and stimulation of GAT-3 uptake of GABA from the extracellular space. In addition to underscoring the importance of dendritically released dopamine in modulating synaptic transmission, our studies demonstrate that dopaminergic modulation of astrocytes plays a key role in modulating SNr circuits and motor behavior. Teaser SNc dopaminergic neurons and astrocytes regulate tonic GABAergic inhibition of SNr neurons. Competing Interest Statement The authors have declared no competing interest. Footnotes Added additional astrocyte and GAT-1/3 experiments. Figures 3, 5, 6, 7 & 8 Revised. https://doi.org/10.5281/zenodo.17296457 Funder Information Declared Aligning Science Across Parkinson's, https://ror.org/03zj4c476 , 020551 Freedom Together Foundation , MR-2021-2960 National Institute of Neurological Disorders and Stroke , NS121174 United States Department of Defense, https://ror.org/0447fe631 , W81XWH2110749 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted April 17, 2026. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about bioRxiv. 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James Surmeier bioRxiv 2024.03.27.586699; doi: https://doi.org/10.1101/2024.03.27.586699 Share This Article: Copy Citation Tools Astrocytes mediate the dopaminergic modulation of tonic GABAergic signaling in substantia nigra DeNard V Simmons , Oscar Andrés Moreno-Ramos , Divya D.A. Raj , Konstantin Kaganovsky , Arin Pamukcu , Nora Vrieler , Tatiana Tkatch , Zhong Xie , Ana Isabel Silva de Sousa , Enrico Zampese , Jun Ding , Rajeshwar Awatramani , Charles J. Wilson , D. 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