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4. Cognitive Impact of Cerebellar Non-invasive Stimulation in a Patient With Schizophrenia

Author

Laidi, Charles, Levenes, Carole, Suarez-Perez, Alex, Février, Caroline, Durand, Florence, Bouaziz, Noomane, Januel, Dominique, Pôle de Psychiatrie [Hôpital Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital H. Mondor - A. Chenevier, IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Unité de recherche en NeuroImagerie Applicative Clinique et Translationnelle (UNIACT), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation FondaMental [Créteil], Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Unité de Recherche Clinique de l'Hôpital de Ville-Evrard [Neuilly-sur-​Marne] (URCVE), Etablissement public de santé de Ville-Evrard (EPS), and Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Psychiatry, cognition, schizophrenia, tDCS—transcranial direct current stimulation, cerebellum, Case Report, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], eyeblink conditioning
Abstract

International audience; Cerebellum plays a role in the regulation of cognitive processes. Cerebellar alterations could explain cognitive impairments in schizophrenia. We describe the case of a 50 years old patient with schizophrenia whom underwent cerebellar transcranial direct current stimulation (tDCS). In order to study the effect of cerebellar stimulation on cognitive functions, the patient underwent a neuropsychological assessment and an eyeblink conditioning (EBC) protocol. Although the effect of brain stimulation cannot be only assessed in a single-case study, our results suggest that cerebellar stimulation may have an effect on a broad range of cognitive functions typically impaired in patients with schizophrenia, including verbal episodic, short term, and working memory. In addition to neuropsychological tests, we evaluated the cerebellar function by performing EBC before and after tDCS. Our data suggest that tDCS can improve EBC. Further clinical trials are required for better understanding of how cerebellar stimulation can modulate cognitive processes in patients with schizophrenia and healthy controls.

Published
2020
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6. Patterned expression of Pannexin channels in the adult mouse cerebellar Purkinje cells

Author

Ady, Visou, Dubayle, David, Le Blanc, Pascale, Shestopalov, Valery, Meunier, Claude, Levenes, Carole, Centre de neurophysique, physiologie, pathologie (UMR 8119), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Bascom Palmer Eye Institute,University of Miami, Miami, FL, USA, and Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Published
2019

7. Cellular mechanisms of cerebellar LTD

Author

Daniel, Herve, Levenes, Carole, and Crepel, Francis

Subjects
Depression, Mental -- Physiological aspects, Cerebellum -- Abnormalities, Motor learning -- Physiological aspects, Neural transmission -- Physiological aspects, Health, Psychology and mental health
Abstract

In the past decade there have been advances in understanding the cellular mechanisms of the long-term depression (LTD) of synaptic transmission at parallel fiber-Purkinje cell synapses in the cerebellum. This review first summarizes current views on mechanisms involved in LTD induction, from activation of voltage-gated [Ca.sup.2+] channels, of ionotropic (AMPA) and metabotropic (mGluRI) glutamate receptors, to stimulation of protein kinase C and nitric oxide formation. Second, we will focus on recent findings that point towards the involvement of [Ca.sup.2+] release from internal stores in LTD induction, localize the sources and targets of nitric oxide and indicate a postsynaptic site for LTD expression. Finally, a role for LTD in motor learning is now well supported by recent experiments on transgenic mice.

Published
1998

8. A subcortical circuit linking the cerebellum to the basal ganglia engaged in vocal learning

Author

Pidoux, Ludivine, Le Blanc, Pascale, Levenes, Carole, Leblois, Arthur, Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Neurophysique et physiologie du système moteur (NPSM), and Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Sound Spectrography, Time Factors, animal structures, cerebellum, QH301-705.5, Deep Brain Stimulation, Science, education, Purkinje Cells, Thalamus, Phonetics, Area X, Neural Pathways, otorhinolaryngologic diseases, Animals, Learning, Biology (General), ComputingMilieux_MISCELLANEOUS, Cerebral Cortex, Neurons, sensorimotor learning, songbirds, respiratory system, nervous system, Synapses, basal ganglia, behavior and behavior mechanisms, Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Finches, Other, Vocalization, Animal, Insight, corticostriatal loops, Research Article, Neuroscience
Abstract

Speech is a complex sensorimotor skill, and vocal learning involves both the basal ganglia and the cerebellum. These subcortical structures interact indirectly through their respective loops with thalamo-cortical and brainstem networks, and directly via subcortical pathways, but the role of their interaction during sensorimotor learning remains undetermined. While songbirds and their song-dedicated basal ganglia-thalamo-cortical circuitry offer a unique opportunity to study subcortical circuits involved in vocal learning, the cerebellar contribution to avian song learning remains unknown. We demonstrate that the cerebellum provides a strong input to the song-related basal ganglia nucleus in zebra finches. Cerebellar signals are transmitted to the basal ganglia via a disynaptic connection through the thalamus and then conveyed to their cortical target and to the premotor nucleus controlling song production. Finally, cerebellar lesions impair juvenile song learning, opening new opportunities to investigate how subcortical interactions between the cerebellum and basal ganglia contribute to sensorimotor learning., eLife digest Human infants learn to speak by imitating the speech of adults around them. Over time, they learn to coordinate movements of their vocal cords and breathing muscles to produce specific sounds. Juvenile songbirds go through a similar process while learning to sing. Fledglings mimic adult birds and each other as they learn to produce their own songs. Songbirds are therefore often used as a model for how the brain drives vocal learning – whether of speech or song. Circuits made up of similar brain regions support vocal learning in infants and in songbirds. These regions include areas of cortex, the outermost layer of the mammalian brain, as well as structures deep below the cortex. The latter include the basal ganglia, a set of structures that help mammals learn and perform fine motor skills. But there is one brain region that has been implicated in vocal learning in infants but not in songbirds. Known as the cerebellum or ‘little brain’, this structure also helps with planning and performing movements. Anatomical studies in songbirds suggest a connection between the cerebellum and song-related circuits. But a direct role in birdsong has never been shown. Pidoux et al. now demonstrate that stimulating the cerebellum in anaesthetized zebra finches activates basal ganglia neurons involved in song learning. This activation spreads through a song-related circuit to neurons controlling the vocal cords. Disrupting the cerebellum, by contrast, makes it harder for juvenile birds to imitate adult song. This is the first direct evidence for a role of the cerebellum in the acquisition of birdsong. Beyond vocal learning, the results shed light on the circuits that support motor learning more generally. They also suggest that we can use songbirds to study the cerebellum and its interactions with the basal ganglia. Abnormal interactions between these regions occur in movement disorders such as Parkinson's disease. Studying these interactions in the healthy mammalian brain should provide clues to the pathology behind these conditions.

Published
2018
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11. Itinéraires Bis: « Mon parcours de jeune chercheur »

Author

Kahn, Axel, Fleuret, Sebastien, Descotes-Genon, Sébastien, B. Garnier, Nicolas, Levenes, Carole, Gurden, hirac, Reiche, Ina, Ginet, Nicolas, Gay, Laurence, Viollet, Cécile, Rogner, Ute Christine, Guillerme, Sylvie, Baaden, Marc, Draelants, Isabelle, Institut Fédératif de Recherche Alfred Jost (IFRAJ), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Espaces et Sociétés (ESO), Le Mans Université (UM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université d'Angers (UA)-AGROCAMPUS OUEST-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Géographie et d'Aménagement Régional de l'Université de Nantes (IGARUN), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de Physique Théorique d'Orsay [Orsay] (LPT), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11), Laboratoire Nicolas Garnier, Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC (UMR_8165)), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche et de restauration des musées de France (C2RMF), Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture et de la Communication (MCC), Biologie végétale et microbiologie environnementale - UMR7265 (BVME), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Droits International, Comparé et Européen/ Institut Louis Favoreu - Groupe d 'études et de recherches sur la justice constitutionnelle [DICE - UMR 7318] (DICE / ILF-GERJC), Droits International, Comparé et Européen (DICE), Centre National de la Recherche Scientifique (CNRS)-Université de Toulon (UTLN)-Université de Pau et des Pays de l'Adour (UPPA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Université de Toulon (UTLN)-Université de Pau et des Pays de l'Adour (UPPA)-Aix Marseille Université (AMU), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Géographie de l'environnement (GEODE), Université Toulouse - Jean Jaurès (UT2J)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie théorique [Paris] (LBT (UPR_9080)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut de Chimie du CNRS (INC), Atelier Vincent de Beauvais, Institut de recherche et d'histoire des textes (IRHT), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire d'Histoire des Sciences et de Philosophie - Archives Henri Poincaré (LHSP), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Centre de Médiévistique Jean-Schneider, Université Nancy 2-Centre National de la Recherche Scientifique (CNRS)-Université Nancy 2-Centre National de la Recherche Scientifique (CNRS), Centre de Médiévistique Jean-Schneider, Université Nancy 2-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)

Subjects
[PHYS]Physics [physics], [SCCO]Cognitive science, [SDV]Life Sciences [q-bio], Chercheurs, [CHIM]Chemical Sciences, [SHS.GEO]Humanities and Social Sciences/Geography, Centre national de la recherche scientifique, [SHS.HIST]Humanities and Social Sciences/History, [SHS]Humanities and Social Sciences
Abstract

Volume collectif de témoignages et de réflexion sur des parcours de 13 chercheurs entrés au CNRS depuis 5 ans. Préface d'Axel Kahn. Introduction par Sébastien Descotes-Genon, Isabelle Draelants, Ute C. Rogner.; International audience; Les chercheurs font rarement la une des journaux : l'annonce des prix Nobel, de rares manifestations, les polémiques de quelques grandes figures médiatiques, la réponse ciblée à une inquiétude suite à un phénomène de société, à cela se résume le plus souvent leur présence sur la scène médiatique. Que signifie être chercheur dans un contexte sociétal mouvant ? Quels sont les plaisirs et les difficultés de ce métier en pleine évolution ? En quoi consiste-t-il ? Comment et pourquoi devient-on chercheur ? Ce livre soulève ces quelques questions par le biais de témoignages de chercheurs d'horizons très divers, récemment recrutés au Centre National de la Recherche Scientifique (CNRS). L'initiative de ce livre est née à la suite de journées d'études axées sur les potentialités des itinéraires professionnels des chercheurs. Celles-ci ont mis en évidence de nombreux points communs malgré la diversité des parcours de « jeunes chercheurs » : des ressentis, des questions, des constats similaires, appuyés pourtant sur des expériences différentes. Les treize auteurs évoquent, au travers de leurs témoignages, toujours passionnés, parfois drôles, souvent émouvants, leurs « itinéraires » de chercheurs.

Published
2009

19. Type 1 metabotropic glutamate receptors (m Glu1) trigger the gating of Glu D2 delta glutamate receptors.

Author

Ady, Visou, Perroy, Julie, Tricoire, Ludovic, Piochon, Claire, Dadak, Selma, Chen, Xiaoru, Dusart, Isabelle, Fagni, Laurent, Lambolez, Bertrand, and Levenes, Carole

Abstract

The orphan Glu D2 receptor belongs to the ionotropic glutamate receptor family but does not bind glutamate. Ligand-gated Glu D2 currents have never been evidenced, and whether Glu D2 operates as an ion channel has been a long-standing question. Here, we show that Glu D2 gating is triggered by type 1 metabotropic glutamate receptors, both in a heterologous expression system and in Purkinje cells. Thus, Glu D2 is not only an adhesion molecule at synapses but also works as a channel. This gating mechanism reveals new properties of glutamate receptors that emerge from their interaction and opens unexpected perspectives regarding synaptic transmission and plasticity. [ABSTRACT FROM AUTHOR]

Published
2014
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23. Novel protective effect of mifepristone on detrimental GABAA receptor activity to immature Purkinje neurons.

Author

Rakotomamonjy, Jennifer, Levenes, Carole, Baulieu, Etienne Emile, Schumacher, Michael, and Ghoumari, Abdel M.

Subjects
*PURKINJE cells, *MIFEPRISTONE, *CEREBELLUM, *GABA, *CAFFEINE, *NEOMYCIN
Abstract

Immature Purkinje neurons are particularly vulnerable cells. They survive in cerebellar slice cultures under treatment by the synthetic steroid mifepristone (RU486) that depolarizes diem at this age. The present study aims at understanding die mechanism underlying this neuroprotective effect. In the developing cerebellum, die role of γ-aminobutyric acid (GABA) in neuron survival is unknown. In 3-d-old mouse cerebellar slice cultures, we show that GABAA receptor activation is depolarizing and excitatory. Antagonists of GABAA receptors rescue Purkinje neurons, demonstrating that GABA is endogenously released hi tins preparation and is toxic. Mifepristone likely protects these neurons by reversing GABAA receptor-mediated chloride fluxes and reducing their driving force. Neuroprotection by mifepristone is dose-dependently decreased by the agonist of GABAA receptors muscimol and by caffeine, an agonist of internal calcium store release. Moreover, the survival induced by neomycin, an inhibitor of calcium release, is partially reversed by muscimol. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB239063 also rescues Purkinje neurons. In summary, we propose that when GABA is depolarizing, mifepristone protects Purkinje neurons by shunting GABA responses and probably chloride fluxes, by inhibiting p38 MAPK activity and likely internal calcium store release. A new and nonhormonal effect of mifepristone is thus revealed. [ABSTRACT FROM AUTHOR]

Published
2011
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24. Short-term retrograde inhibition of GABAergic synaptic currents in rat purkinje cells is mediated by endogenous cannabinoids

Author

Ken Mackie, Alain Marty, Marco A. Diana, Carole Levenes, Levenes, Carole, Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
Patch-Clamp Techniques, Cannabinoid receptor, Receptors, Drug, medicine.medical_treatment, Action Potentials, MESH: gamma-Aminobutyric Acid, MESH: Cannabinoids, Synaptic Transmission, Membrane Potentials, Purkinje Cells, 0302 clinical medicine, Piperidines, MESH: Receptors, Cannabinoid, Cerebellum, MESH: Presynaptic Terminals, MESH: Animals, MESH: Neuronal Plasticity, Receptors, Cannabinoid, gamma-Aminobutyric Acid, MESH: Action Potentials, 0303 health sciences, Neuronal Plasticity, General Neuroscience, Glutamate receptor, MESH: Naphthalenes, MESH: Neural Inhibition, MESH: Interneurons, MESH: Piperidines, MESH: Benzoxazines, GABAergic, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Rats, Morpholines, Presynaptic Terminals, MESH: Morpholines, In Vitro Techniques, Naphthalenes, Neurotransmission, Biology, MESH: Calcium Signaling, 03 medical and health sciences, MESH: Purkinje Cells, Interneurons, MESH: Receptors, Drug, MESH: Patch-Clamp Techniques, medicine, MESH: Synaptic Transmission, Animals, MESH: Membrane Potentials, Calcium Signaling, Patch clamp, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ARTICLE, 030304 developmental biology, MESH: In Vitro Techniques, Cannabinoids, Neural Inhibition, MESH: Cerebellum, Benzoxazines, Rats, Somatodendritic compartment, Retrograde signaling, Pyrazoles, Cannabinoid, Neuroscience, 030217 neurology & neurosurgery, MESH: Pyrazoles
Abstract

Depolarization-induced suppression of inhibition (DSI) is a form of short-term plasticity of GABAergic synaptic transmission that is found in cerebellar Purkinje cells and hippocampal CA1 pyramidal cells. DSI involves the release of a calcium-dependent retrograde messenger by the somatodendritic compartment of the postsynaptic cell. Both glutamate and endogenous cannabinoids have been proposed as retrograde messenger.Here we show that, in cerebellar parasagittal slices, type 1 cannabinoid receptors (CB1Rs) are expressed at high levels in axons of GABAergic interneurons and in presynaptic terminals onto Purkinje cells. Application of the cannabinoid antagonist AM-251 (500 nm) leads to the abolition of the DSI of evoked currents (eIPSCs) recorded in paired recordings and to a strong reduction of the DSI of TTX-insensitive miniature events (mIPSCs) recorded from Purkinje cells. Furthermore, the CB1R agonist WIN 55–212,2 (5 μm) induces a presynaptic inhibition of synaptic currents similar to that occurring during DSI, as well as an occlusion of DSI after stimulation of Purkinje cells. Moreover, WIN 55–212,2 reduces the calcium transients evoked in presumed presynaptic varicosities by short trains of action potentials.Our results indicate that DSI is mediated by the activation of presynaptic CB1Rs and that an endogenous cannabinoid is a likely candidate retrograde messenger in this preparation. They further suggest that DSI involves distinct presynaptic modifications for eIPSCs and mIPSCs, including an inhibition of action potential-evoked calcium rises.

25. Cognitive Impact of Cerebellar Non-invasive Stimulation in a Patient With Schizophrenia.

Author

Laidi C, Levenes C, Suarez-Perez A, Février C, Durand F, Bouaziz N, and Januel D

Abstract

Cerebellum plays a role in the regulation of cognitive processes. Cerebellar alterations could explain cognitive impairments in schizophrenia. We describe the case of a 50 years old patient with schizophrenia whom underwent cerebellar transcranial direct current stimulation (tDCS). In order to study the effect of cerebellar stimulation on cognitive functions, the patient underwent a neuropsychological assessment and an eyeblink conditioning (EBC) protocol. Although the effect of brain stimulation cannot be only assessed in a single-case study, our results suggest that cerebellar stimulation may have an effect on a broad range of cognitive functions typically impaired in patients with schizophrenia, including verbal episodic, short term, and working memory. In addition to neuropsychological tests, we evaluated the cerebellar function by performing EBC before and after tDCS. Our data suggest that tDCS can improve EBC. Further clinical trials are required for better understanding of how cerebellar stimulation can modulate cognitive processes in patients with schizophrenia and healthy controls., (Copyright © 2020 Laidi, Levenes, Suarez-Perez, Février, Durand, Bouaziz and Januel.)

Published
2020
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26. Novel protective effect of mifepristone on detrimental GABAA receptor activity to immature Purkinje neurons.

Author

Rakotomamonjy J, Levenes C, Baulieu EE, Schumacher M, and Ghoumari AM

Subjects
Animals, Caffeine pharmacology, Chlorides metabolism, Imidazoles pharmacology, Mice, Muscimol pharmacology, Pyrimidines pharmacology, Receptors, GABA-A drug effects, gamma-Aminobutyric Acid physiology, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors, Mifepristone pharmacology, Purkinje Cells drug effects, Purkinje Cells physiology, Receptors, GABA-A physiology
Abstract

Immature Purkinje neurons are particularly vulnerable cells. They survive in cerebellar slice cultures under treatment by the synthetic steroid mifepristone (RU486) that depolarizes them at this age. The present study aims at understanding the mechanism underlying this neuroprotective effect. In the developing cerebellum, the role of γ-aminobutyric acid (GABA) in neuron survival is unknown. In 3-d-old mouse cerebellar slice cultures, we show that GABA(A) receptor activation is depolarizing and excitatory. Antagonists of GABA(A) receptors rescue Purkinje neurons, demonstrating that GABA is endogenously released in this preparation and is toxic. Mifepristone likely protects these neurons by reversing GABA(A) receptor-mediated chloride fluxes and reducing their driving force. Neuroprotection by mifepristone is dose-dependently decreased by the agonist of GABA(A) receptors muscimol and by caffeine, an agonist of internal calcium store release. Moreover, the survival induced by neomycin, an inhibitor of calcium release, is partially reversed by muscimol. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB239063 also rescues Purkinje neurons. In summary, we propose that when GABA is depolarizing, mifepristone protects Purkinje neurons by shunting GABA responses and probably chloride fluxes, by inhibiting p38 MAPK activity and likely internal calcium store release. A new and nonhormonal effect of mifepristone is thus revealed.

Published
2011
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