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Striatal dual cholinergic /GABAergic transmission in Parkinson disease: friends or foes?

The rule of one terminal and one transmitter acting on one synapse clearly fails to cover the complexity of chemical synapse operation in the brain. Compelling evidence now indicates that two transmitters can be released from the same terminal, acting in a complementary manner to generate complex el...

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Autores principales: Lozovaya, Natalia, Ben-Ari, Yehezkel, Hammond, Constance
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Shared Science Publishers OG 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551683/
https://www.ncbi.nlm.nih.gov/pubmed/31225481
http://dx.doi.org/10.15698/cst2018.06.142
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author Lozovaya, Natalia
Ben-Ari, Yehezkel
Hammond, Constance
author_facet Lozovaya, Natalia
Ben-Ari, Yehezkel
Hammond, Constance
author_sort Lozovaya, Natalia
collection PubMed
description The rule of one terminal and one transmitter acting on one synapse clearly fails to cover the complexity of chemical synapse operation in the brain. Compelling evidence now indicates that two transmitters can be released from the same terminal, acting in a complementary manner to generate complex electrical activity in the targets. Our laboratory now showed that a subpopulation striatal cholinergic neurons also release the classical inhibitory transmitter GABA with a balance between excitation and inhibition being provided by acetylcholine and GABA, respectively. An illustration of the importance of this dual release comes from the fact that when dopamine signals are absent such as in Parkinson disease (PD) the GABAergic inhibition in these dual cholinergic/GABAergic cells fails because of high intracellular chloride ((Cl(-))(I)) levels rendering the cholinergic excitatory component unmet by a parallel inhibitory drive. Restoring low (Cl(-))(I) with the NKCC1 chloride importer antagonist bumetanide attenuates the electrical and motor disturbance. In addition to illustrating the complex interactions between two transmitters acting at the same synapse, this study paves the way to novel conceptual treatment of PD based on restoration of GABAergic inhibition in keeping with our pilot clinical trial showing indeed that bumetanide together with levodopa attenuates axial motor disturbance. It is also in keeping with extensive investigations showing increased (Cl(-))(I) levels and weakened inhibition in a wide range of pathological insults and their restoration by bumetanide. It raises fundamental issues related to the operation of the striatum and basal ganglia in health and disease.
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spelling pubmed-65516832019-06-20 Striatal dual cholinergic /GABAergic transmission in Parkinson disease: friends or foes? Lozovaya, Natalia Ben-Ari, Yehezkel Hammond, Constance Cell Stress Microreview The rule of one terminal and one transmitter acting on one synapse clearly fails to cover the complexity of chemical synapse operation in the brain. Compelling evidence now indicates that two transmitters can be released from the same terminal, acting in a complementary manner to generate complex electrical activity in the targets. Our laboratory now showed that a subpopulation striatal cholinergic neurons also release the classical inhibitory transmitter GABA with a balance between excitation and inhibition being provided by acetylcholine and GABA, respectively. An illustration of the importance of this dual release comes from the fact that when dopamine signals are absent such as in Parkinson disease (PD) the GABAergic inhibition in these dual cholinergic/GABAergic cells fails because of high intracellular chloride ((Cl(-))(I)) levels rendering the cholinergic excitatory component unmet by a parallel inhibitory drive. Restoring low (Cl(-))(I) with the NKCC1 chloride importer antagonist bumetanide attenuates the electrical and motor disturbance. In addition to illustrating the complex interactions between two transmitters acting at the same synapse, this study paves the way to novel conceptual treatment of PD based on restoration of GABAergic inhibition in keeping with our pilot clinical trial showing indeed that bumetanide together with levodopa attenuates axial motor disturbance. It is also in keeping with extensive investigations showing increased (Cl(-))(I) levels and weakened inhibition in a wide range of pathological insults and their restoration by bumetanide. It raises fundamental issues related to the operation of the striatum and basal ganglia in health and disease. Shared Science Publishers OG 2018-05-27 /pmc/articles/PMC6551683/ /pubmed/31225481 http://dx.doi.org/10.15698/cst2018.06.142 Text en Copyright: © 2018 Lozovaya et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
spellingShingle Microreview
Lozovaya, Natalia
Ben-Ari, Yehezkel
Hammond, Constance
Striatal dual cholinergic /GABAergic transmission in Parkinson disease: friends or foes?
title Striatal dual cholinergic /GABAergic transmission in Parkinson disease: friends or foes?
title_full Striatal dual cholinergic /GABAergic transmission in Parkinson disease: friends or foes?
title_fullStr Striatal dual cholinergic /GABAergic transmission in Parkinson disease: friends or foes?
title_full_unstemmed Striatal dual cholinergic /GABAergic transmission in Parkinson disease: friends or foes?
title_short Striatal dual cholinergic /GABAergic transmission in Parkinson disease: friends or foes?
title_sort striatal dual cholinergic /gabaergic transmission in parkinson disease: friends or foes?
topic Microreview
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551683/
https://www.ncbi.nlm.nih.gov/pubmed/31225481
http://dx.doi.org/10.15698/cst2018.06.142
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