Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake
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Abstract
ABSTRACT Dopamine (DA)-releasing neurons in the substantia nigra pars compacta (SNc DA ) inhibit target cells in the striatum through postsynaptic activation of γ-aminobutyric acid (GABA) receptors. However, the molecular mechanisms responsible for GABAergic signaling remain unclear, as SNc DA neurons lack enzymes typically required to produce GABA or package it into synaptic vesicles. Here we show that aldehyde dehydrogenase 1a1 (Aldh1a1), an enzyme proposed to function as a GABA synthetic enzyme in SNc DA neurons does not produce GABA for synaptic transmission. Instead, we demonstrate that SNc DA axons obtain GABA exclusively through presynaptic uptake using the membrane GABA transporter Gat1 (encoded by Slc6a1 ). GABA is then packaged for vesicular release using the vesicular monoamine transporter Vmat2. Our data therefore show that presynaptic transmitter recycling can substitute for de novo GABA synthesis and that Vmat2 contributes to vesicular GABA transport, expanding the range of molecular mechanisms available to neurons to support inhibitory synaptic communication.
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The assignment of neurotransmitter types based on synthesizing enzymes and transporter genes is conservative; there may be even more diversity in neurotransmitter co-release patterns if other unconventional transmitter release routes are considered.
“Of note, our assignment of neurotransmitter types based on synthesizing enzymes and transporter genes is conservative; there may be even more diversity in neurotransmitter co-release patterns if other unconventional transmitter release routes are considered57,118.”
From A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain (2023) · cites this paper as [118]
A reported unconventional mechanism underlying co-transmission of dopamine and GABA by SNc dopaminergic neurons in STR does not depend on cell-autonomous GABA synthesis but on presynaptic uptake through Slc6a1 while still relying on Slc18a2 for synaptic GABA release, which could make Aldh1a1 unnecessary.
“Of note, a reported unconventional mechanism118 underlying co-transmission of dopamine and GABA by SNc dopaminergic neurons in the STR does not depend on cell-autonomous GABA synthesis but instead on presynaptic uptake from the extracellular space through the GABA transporter Slc6a1 (Gat1) while still relying on Slc18a2 for synaptic GABA release, which could make Aldh1a1 unnecessary in these cells”
From A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain (2023) · cites this paper as [118]
GAT1 is both necessary and sufficient to sustain GABA release in DANs.
“only the GABA transporter, GAT1, is both necessary and sufficient to sustain GABA release in DANs”
From Synaptic and circuit functions of multitransmitter neurons in the mammalian brain (2023) · cites this paper as [118]
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Dopamine Triggers Heterosynaptic Plasticity
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GABA is localized in dopaminergic synaptic vesicles in the rodent striatum
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GABA reverse transport by the neuronal cotransporter GAT1: influence of internal chloride depletion
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How alcohol affects motor control: not your usual suspects
Melani, R., & Tritsch, N. X. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00355-1 · Cited by 3 · see citing works
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A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain
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Role of GABA pathway in motor and non-motor symptoms in Parkinson's disease: a bidirectional circuit
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Sleep disorders cause Parkinson's disease or the reverse is true: Good GABA good night
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The dopamine neuron synaptic map in the striatum
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Self-citationAlterations in neurotransmitter co-release in Parkinson's disease
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Protein composition of axonal dopamine release sites in the striatum
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Conditional deletion of neurexins dysregulates neurotransmission from dopamine neurons
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The Role of GABA Pathway Components in Pathogenesis of Neurodevelopmental Disorders
Marilovtseva, E. V., Abdurazakov, A., Kurishev, A. O., Mikhailova, V. A., & Голимбет, В. Е. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199492 · Cited by 20 · see citing works
Widespread co-release of glutamate and GABA throughout the mouse brain
Ceballos, C. C., Ma, L., Qin, M., & Zhong, H. (2024) · Communications Biology · doi:10.1038/s42003-024-07198-y · Cited by 19 · see citing works
Harada, M., Capdevila, L. S., Wilhelm, M., Burdakov, D., & Patriarchi, T. (2023) · eLife · doi:10.7554/elife.90158 · Cited by 13 · see citing works
Qian, J., Zheng, L. P., Hong, Z., & Zhao, M. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c07140 · Cited by 14 · see citing works
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Analytical approaches to examine gamma-aminobutyric acid and glutamate vesicular co-packaging
Kim, S., & Sabatini, B. L. (2023) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2022.1076616 · Cited by 10 · see citing works
Subsecond dopamine fluctuations do not specify the vigor of ongoing actions
Liu, H., Melani, R., Maltese, M., Taniguchi, J., Sankaramanchi, A., Zeng, R., Martin, J. R., & Tritsch, N. X. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02102-1 · Cited by 10 · see citing works
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Fast neurotransmitter identity of MCH neurons: Do contents depend on context?
Beekly, B. G., Rupp, A. C., Burgess, C. R., & Elias, C. F. (2023) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2023.101069 · Cited by 9 · see citing works
Molecular diversity and migration of GABAergic neurons in the developing ventral midbrain
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Arcuate dopaminergic/GABAergic neurons project within the hypothalamus and to the median eminence
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Prevalent co-release of glutamate and GABA throughout the mouse brainPreprint
Ceballos, C. C., Ma, L., Qin, M., & Zhong, H. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.27.587069 · Cited by 3 · see citing works
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Astrocytes mediate the dopaminergic modulation of tonic GABAergic signaling in substantia nigraPreprint
Simmons, D. V., Moreno-Ramos, O. A., Raj, D. D. A., Kaganovsky, K., Pamukcu, A., Vrieler, N., Tkatch, T., Xie, Z., de Sousa, A. I. S., Zampese, E., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.27.586699 · Cited by 2 · see citing works
Nitrogen waste metabolism as a locus of nitrergic co-transmission in the brain
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Molecular heterogeneity of midbrain dopamine neurons
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Anatomy of dopamine neuron projections: Axonal arbors, varicosities, and synapses
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Astrocytes mediate the dopaminergic modulation of tonic GABAergic signaling in substantia nigra
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High-resolution mri guided whole mouse brain neuronal cell type atlas using deep learning
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- Authors
- Melani, R., & Tritsch, N. X.
- Affiliations
- NYU Langone Health (US)
- Corresponding author
- Tritsch, Nicolas X.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2022-04
- Volume
- 39
- Issue
- 3
- Pages
- 110716
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC9097974
- OpenAlex
- W4226020367
- Cited by
- 56
- References
- 94
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 18 · 2023: 15 · 2022: 2
- FWCI
- 5.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- SSRN Electronic Journal (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- Funders
- Alfred P Sloan Foundation
- Dana Foundation
- Whitehall Foundation
- National Institutes of Health (DP2NS105553)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- midbrain dopaminergic neurons, substantia nigra pars compacta, GABAergic inhibition, ALDH1A1, SLC6A1, GABA transporters, vesicular monoamine transporter 2, striatum, synaptic vesicle recycling
- MeSH terms
- Corpus Striatum, Dopamine, gamma-Aminobutyric Acid, Mesencephalon, Substantia Nigra, Dopaminergic Neurons
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