GAT-3 Dysfunction Generates Tonic Inhibition in External Globus Pallidus Neurons in Parkinsonian Rodents

Summary: The external globus pallidus (GP) is a key GABAergic hub in the basal ganglia (BG) circuitry, a neuronal network involved in motor control. In Parkinson’s disease (PD), the rate and pattern of activity of GP neurons are profoundly altered and contribute to the motor symptoms of the disease....

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Main Authors: Marine Chazalon, Elena Paredes-Rodriguez, Stéphanie Morin, Audrey Martinez, Sofia Cristóvão-Ferreira, Sandra Vaz, Ana Sebastiao, Aude Panatier, Eric Boué-Grabot, Cristina Miguelez, Jérôme Baufreton
Format: Article
Language:English
Published: Elsevier 2018-05-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124718305436
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spelling doaj-6b65f540e82340889cacf467ae4948ef2020-11-24T22:01:13ZengElsevierCell Reports2211-12472018-05-0123616781690GAT-3 Dysfunction Generates Tonic Inhibition in External Globus Pallidus Neurons in Parkinsonian RodentsMarine Chazalon0Elena Paredes-Rodriguez1Stéphanie Morin2Audrey Martinez3Sofia Cristóvão-Ferreira4Sandra Vaz5Ana Sebastiao6Aude Panatier7Eric Boué-Grabot8Cristina Miguelez9Jérôme Baufreton10Université de Bordeaux, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France; CNRS UMR 5293, Institut des Maladies Neurodégénératives, 33000 Bordeaux, FranceDepartment of Pharmacology, University of the Basque Country (UPV/EHU), 48940 Leioa, SpainUniversité de Bordeaux, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France; CNRS UMR 5293, Institut des Maladies Neurodégénératives, 33000 Bordeaux, FranceUniversité de Bordeaux, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France; CNRS UMR 5293, Institut des Maladies Neurodégénératives, 33000 Bordeaux, FranceInstitute of Pharmacology and Neurosciences, Faculty of Medicine, and Unit of Neuroscience, Institute of Molecular Medicine, University of Lisbon, Lisbon, PortugalInstitute of Pharmacology and Neurosciences, Faculty of Medicine, and Unit of Neuroscience, Institute of Molecular Medicine, University of Lisbon, Lisbon, PortugalInstitute of Pharmacology and Neurosciences, Faculty of Medicine, and Unit of Neuroscience, Institute of Molecular Medicine, University of Lisbon, Lisbon, PortugalINSERM U1215, Neurocentre Magendie, 33000 Bordeaux, France; Université de Bordeaux, 33000 Bordeaux, FranceUniversité de Bordeaux, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France; CNRS UMR 5293, Institut des Maladies Neurodégénératives, 33000 Bordeaux, FranceDepartment of Pharmacology, University of the Basque Country (UPV/EHU), 48940 Leioa, SpainUniversité de Bordeaux, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France; CNRS UMR 5293, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France; Corresponding authorSummary: The external globus pallidus (GP) is a key GABAergic hub in the basal ganglia (BG) circuitry, a neuronal network involved in motor control. In Parkinson’s disease (PD), the rate and pattern of activity of GP neurons are profoundly altered and contribute to the motor symptoms of the disease. In rodent models of PD, the striato-pallidal pathway is hyperactive, and extracellular GABA concentrations are abnormally elevated in the GP, supporting the hypothesis of an alteration of neuronal and/or glial clearance of GABA. Here, we discovered the existence of persistent GABAergic tonic inhibition in GP neurons of dopamine-depleted (DD) rodent models. We showed that glial GAT-3 transporters are downregulated while neuronal GAT-1 function remains normal in DD rodents. Finally, we showed that blocking GAT-3 activity in vivo alters the motor coordination of control rodents, suggesting that GABAergic tonic inhibition in the GP contributes to the pathophysiology of PD. : The globus pallidus (GP) is a key basal ganglia nucleus involved in motor control. In Parkinson’s disease, the cellular mechanisms underlying GP neuron hypoactivity are poorly understood. Chazalon et al. find that glial GABA transporters are downregulated in parkinsonian rodents, leading to aberrant GABAergic inhibition in the GP and motor coordination impairment. Keywords: tonic inhibition, basal ganglia, extrasynaptic GABAA receptors, GABA transporters, electrophysiologyhttp://www.sciencedirect.com/science/article/pii/S2211124718305436
collection DOAJ
language English
format Article
sources DOAJ
author Marine Chazalon
Elena Paredes-Rodriguez
Stéphanie Morin
Audrey Martinez
Sofia Cristóvão-Ferreira
Sandra Vaz
Ana Sebastiao
Aude Panatier
Eric Boué-Grabot
Cristina Miguelez
Jérôme Baufreton
spellingShingle Marine Chazalon
Elena Paredes-Rodriguez
Stéphanie Morin
Audrey Martinez
Sofia Cristóvão-Ferreira
Sandra Vaz
Ana Sebastiao
Aude Panatier
Eric Boué-Grabot
Cristina Miguelez
Jérôme Baufreton
GAT-3 Dysfunction Generates Tonic Inhibition in External Globus Pallidus Neurons in Parkinsonian Rodents
Cell Reports
author_facet Marine Chazalon
Elena Paredes-Rodriguez
Stéphanie Morin
Audrey Martinez
Sofia Cristóvão-Ferreira
Sandra Vaz
Ana Sebastiao
Aude Panatier
Eric Boué-Grabot
Cristina Miguelez
Jérôme Baufreton
author_sort Marine Chazalon
title GAT-3 Dysfunction Generates Tonic Inhibition in External Globus Pallidus Neurons in Parkinsonian Rodents
title_short GAT-3 Dysfunction Generates Tonic Inhibition in External Globus Pallidus Neurons in Parkinsonian Rodents
title_full GAT-3 Dysfunction Generates Tonic Inhibition in External Globus Pallidus Neurons in Parkinsonian Rodents
title_fullStr GAT-3 Dysfunction Generates Tonic Inhibition in External Globus Pallidus Neurons in Parkinsonian Rodents
title_full_unstemmed GAT-3 Dysfunction Generates Tonic Inhibition in External Globus Pallidus Neurons in Parkinsonian Rodents
title_sort gat-3 dysfunction generates tonic inhibition in external globus pallidus neurons in parkinsonian rodents
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2018-05-01
description Summary: The external globus pallidus (GP) is a key GABAergic hub in the basal ganglia (BG) circuitry, a neuronal network involved in motor control. In Parkinson’s disease (PD), the rate and pattern of activity of GP neurons are profoundly altered and contribute to the motor symptoms of the disease. In rodent models of PD, the striato-pallidal pathway is hyperactive, and extracellular GABA concentrations are abnormally elevated in the GP, supporting the hypothesis of an alteration of neuronal and/or glial clearance of GABA. Here, we discovered the existence of persistent GABAergic tonic inhibition in GP neurons of dopamine-depleted (DD) rodent models. We showed that glial GAT-3 transporters are downregulated while neuronal GAT-1 function remains normal in DD rodents. Finally, we showed that blocking GAT-3 activity in vivo alters the motor coordination of control rodents, suggesting that GABAergic tonic inhibition in the GP contributes to the pathophysiology of PD. : The globus pallidus (GP) is a key basal ganglia nucleus involved in motor control. In Parkinson’s disease, the cellular mechanisms underlying GP neuron hypoactivity are poorly understood. Chazalon et al. find that glial GABA transporters are downregulated in parkinsonian rodents, leading to aberrant GABAergic inhibition in the GP and motor coordination impairment. Keywords: tonic inhibition, basal ganglia, extrasynaptic GABAA receptors, GABA transporters, electrophysiology
url http://www.sciencedirect.com/science/article/pii/S2211124718305436
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