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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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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