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Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake

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...

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Detalles Bibliográficos
Autores principales: Melani, Riccardo, Tritsch, Nicolas X.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097974/
https://www.ncbi.nlm.nih.gov/pubmed/35443174
http://dx.doi.org/10.1016/j.celrep.2022.110716
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author Melani, Riccardo
Tritsch, Nicolas X.
author_facet Melani, Riccardo
Tritsch, Nicolas X.
author_sort Melani, Riccardo
collection PubMed
description 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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spelling pubmed-90979742022-05-12 Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake Melani, Riccardo Tritsch, Nicolas X. Cell Rep Article 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. 2022-04-19 /pmc/articles/PMC9097974/ /pubmed/35443174 http://dx.doi.org/10.1016/j.celrep.2022.110716 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Melani, Riccardo
Tritsch, Nicolas X.
Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake
title Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake
title_full Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake
title_fullStr Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake
title_full_unstemmed Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake
title_short Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake
title_sort inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic gaba uptake
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097974/
https://www.ncbi.nlm.nih.gov/pubmed/35443174
http://dx.doi.org/10.1016/j.celrep.2022.110716
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