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2. Nanoscopic distribution of VAChT and VGLUT3 in striatal cholinergic varicosities suggests colocalization and segregation of the two transporters in synaptic vesicles

Author

Cristofari, Paola, Desplanque, Mazarine, Poirel, Odile, Hébert, Alison, Dumas, Sylvie, Herzog, Etienne, Danglot, Lydia, Geny, David, Gilles, Jean-François, Geeverding, Audrey, Bolte, Susanne, Canette, Alexis, Trichet, Michaël, Fabre, Véronique, Daumas, Stéphanie, Pietrancosta, Nicolas, Mestikawy, Salah El, and Bernard, Véronique

Subjects
Quantitative Biology - Neurons and Cognition
Abstract

Striatal cholinergic interneurons (CINs) use acetylcholine (ACh) and glutamate (Glut) to regulate the striatal network since they express vesicular transporters for ACh (VAChT) and Glut (VGLUT3). However, whether ACh and Glut are released simultaneously and/or independently from cholinergic varicosities is an open question. The answer to that question requires the multichannel detection of vesicular transporters at the level of single synaptic vesicle (SV). Here, we used super-resolution STimulated Emission Depletion microscopy (STED) to characterize and quantify the distribution of VAChT and VGLUT3 in CINs SVs. Nearest-neighbor distances analysis between VAChT and VGLUT3-immunofluorescent spots revealed that 34% of CINs SVs contain both VAChT and VGLUT3. In addition, 40% of SVs expressed only VAChT while 26% of SVs contain only VGLUT3. These results suggest that SVs from CINs have the potential to store simultaneously or independently ACh and/or Glut. Overall, these morphological findings support the notion that CINs varicosities can signal with either ACh or Glut or both with an unexpected level of complexity.

Published
2022
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7. The NeuroD6 subtype of VTA neurons contributes to psychostimulant sensitization and behavioral reinforcement

Author

Bimpisidis, Zisis, König, Niclas, Stagkourakis, Stefanos, Zell, Vivien, Vlcek, Bianca, Dumas, Sylvie, Giros, Bruno, Broberger, Christian, Hnasko, Thomas S, and Wallén-Mackenzie, Åsa

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Substance Misuse, Mental Health, Basic Behavioral and Social Science, Genetics, Behavioral and Social Science, Drug Abuse (NIDA only), Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Amphetamine, Animals, Basic Helix-Loop-Helix Transcription Factors, Central Nervous System Stimulants, Cocaine, Corpus Striatum, Dopaminergic Neurons, Ethanol, Female, Locomotion, Male, Mice, Knockout, Nerve Tissue Proteins, Optogenetics, RNA, Messenger, Reward, Ventral Tegmental Area, Vesicular Monoamine Transport Proteins, accumbens, dopamine, mouse genetics, optogenetics, reward, ventral tegmental area
Abstract

Reward-related behavior is complex and its dysfunction correlated with neuropsychiatric illness. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been associated with different aspects of reward function, but it remains to be disentangled how distinct VTA DA neurons contribute to the full range of behaviors ascribed to the VTA. Here, a recently identified subtype of VTA neurons molecularly defined by NeuroD6 (NEX1M) was addressed. Among all VTA DA neurons, less than 15% were identified as positive for NeuroD6. In addition to dopaminergic markers, sparse NeuroD6 neurons expressed the vesicular glutamate transporter 2 (Vglut2) gene. To achieve manipulation of NeuroD6 VTA neurons, NeuroD6(NEX)-Cre-driven mouse genetics and optogenetics were implemented. First, expression of vesicular monoamine transporter 2 (VMAT2) was ablated to disrupt dopaminergic function in NeuroD6 VTA neurons. Comparing Vmat2lox/lox;NEX-Cre conditional knock-out (cKO) mice with littermate controls, it was evident that baseline locomotion, preference for sugar and ethanol, and place preference upon amphetamine-induced and cocaine-induced conditioning were similar between genotypes. However, locomotion upon repeated psychostimulant administration was significantly elevated above control levels in cKO mice. Second, optogenetic activation of NEX-Cre VTA neurons was shown to induce DA release and glutamatergic postsynaptic currents within the nucleus accumbens. Third, optogenetic stimulation of NEX-Cre VTA neurons in vivo induced significant place preference behavior, while stimulation of VTA neurons defined by Calretinin failed to cause a similar response. The results show that NeuroD6 VTA neurons exert distinct regulation over specific aspects of reward-related behavior, findings that contribute to the current understanding of VTA neurocircuitry.

Published
2019

15. GPR56/ADGRG1 is associated with response to antidepressant treatment

Author

Belzeaux, Raoul, Gorgievski, Victor, Fiori, Laura M., Lopez, Juan Pablo, Grenier, Julien, Lin, Rixing, Nagy, Corina, Ibrahim, El Chérif, Gascon, Eduardo, Courtet, Philippe, Richard-Devantoy, Stéphane, Berlim, Marcelo, Chachamovich, Eduardo, Théroux, Jean-François, Dumas, Sylvie, Giros, Bruno, Rotzinger, Susan, Soares, Claudio N., Foster, Jane A., Mechawar, Naguib, Tall, Gregory G., Tzavara, Eleni T., Kennedy, Sidney H., and Turecki, Gustavo

Published
2020
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16. Antidepressive effects of targeting ELK-1 signal transduction

Author

Apazoglou, Kallia, Farley, Séverine, Gorgievski, Victor, Belzeaux, Raoul, Lopez, Juan Pablo, Grenier, Julien, Ibrahim, El Chérif, El Khoury, Marie-Anne, Tse, Yiu C., Mongredien, Raphaele, Barbé, Alexandre, de Macedo, Carlos E. A., Jaworski, Wojciech, Bochereau, Ariane, Orrico, Alejandro, Isingrini, Elsa, Guinaudie, Chloé, Mikasova, Lenka, Louis, Franck, Gautron, Sophie, Groc, Laurent, Massaad, Charbel, Yildirim, Ferah, Vialou, Vincent, Dumas, Sylvie, Marti, Fabio, Mechawar, Naguib, Morice, Elise, Wong, Tak P., Caboche, Jocelyne, Turecki, Gustavo, Giros, Bruno, and Tzavara, Eleni T.

Published
2018
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18. Anatomical characterisation of three different psychosurgical targets in the subthalamic area: from the basal ganglia to the limbic system

Author

Santin, Marie Neiges, primary, Tempier, Nicolas, additional, Belaid, Hayat, additional, Zenoni, Matthieu, additional, Dumas, Sylvie, additional, Wallén-Mackenzie, Åsa, additional, Bardinet, Eric, additional, Destrieux, Christophe, additional, François, Chantal, additional, and KARACHI, Carine, additional

Published
2023
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19. Nanoscopic distribution of VAChT and VGLUT3 in striatal cholinergic varicosities suggests colocalization and segregation of the two transporters in synaptic vesicles

Author

Cristofari, Paola, primary, Desplanque, Mazarine, additional, Poirel, Odile, additional, Hébert, Alison, additional, Dumas, Sylvie, additional, Herzog, Etienne, additional, Danglot, Lydia, additional, Geny, David, additional, Gilles, Jean-François, additional, Geeverding, Audrey, additional, Bolte, Susanne, additional, Canette, Alexis, additional, Trichet, Michaël, additional, Fabre, Véronique, additional, Daumas, Stéphanie, additional, Pietrancosta, Nicolas, additional, El Mestikawy, Salah, additional, and Bernard, Véronique, additional

Published
2022
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21. Unexpected contributions of striatal projection neurons coexpressing dopamine D1 and D2 receptors in balancing motor control

Author

Bonnavion, Patricia, primary, Varin, Christophe, additional, Fakhfouri, Ghazal, additional, Olondo, Pilar Martinez, additional, De Groote, Aurélie, additional, Cornil, Amandine, additional, Lopez, Ramiro Lorenzo, additional, Fernandez, Elisa Pozuelo, additional, Isingrini, Elsa, additional, Rainer, Quentin, additional, Xu, Kathleen, additional, Tzavara, Eleni, additional, Vigneault, Erika, additional, Dumas, Sylvie, additional, de Kerchove d’Exaerde, Alban, additional, and Giros, Bruno, additional

Published
2022
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24. Nicotinic Acetylcholine Receptors Expressed by Striatal Interneurons Inhibit Striatal Activity and Control Striatal-Dependent Behaviors

Author

Abbondanza, Alice, primary, Ribeiro Bas, Irina, additional, Modrak, Martin, additional, Capek, Martin, additional, Minich, Jessica, additional, Tyshkevich, Alexandra, additional, Naser, Shahed, additional, Rangotis, Revan, additional, Houdek, Pavel, additional, Sumova, Alena, additional, Dumas, Sylvie, additional, Bernard, Veronique, additional, and Janickova, Helena, additional

Published
2022
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27. Midbrain Dopamine Neurons Defined by TrpV1 Modulate Psychomotor Behavior

Author

Serra, Gian Pietro, Guillaumin, Adriane, Dumas, Sylvie, Vlcek, Bianca, Wallén-Mackenzie, Åsa, Serra, Gian Pietro, Guillaumin, Adriane, Dumas, Sylvie, Vlcek, Bianca, and Wallén-Mackenzie, Åsa

Abstract

Dopamine (DA) neurons of the ventral tegmental area (VTA) continue to gain attention as far more heterogeneous than previously realized. Within the medial aspect of the VTA, the unexpected presence of TrpV1 mRNA has been identified. TrpV1 encodes the Transient Receptor Potential cation channel subfamily V member 1, TRPV1, also known as the capsaicin receptor, well recognized for its role in heat and pain processing by peripheral neurons. In contrast, the brain distribution of TrpV1 has been debated. Here, we hypothesized that the TrpV1+ identity defines a distinct subpopulation of VTA DA neurons. To explore these brain TrpV1+ neurons, histological analyses and Cre-driven mouse genetics were employed. TrpV1 mRNA was most strongly detected at the perinatal stage forming a band of scattered neurons throughout the medial VTA, reaching into the posterior hypothalamus. Within the VTA, the majority of TrpV1 co-localized with both Tyrosine hydroxylase (Th) and Vesicular monoamine transporter 2 (Vmat2), confirming a DA phenotype. However, TrpV1 also co-localized substantially with Vesicular glutamate transporter 2 (Vglut2), representing the capacity for glutamate (GLU) release. These TrpV1+/Th+/Vglut2+/Vmat2+ neurons thus constitute a molecularly and anatomically distinct subpopulation of DA-GLU co-releasing neurons. To assess behavioral impact, a TrpV1Cre-driven strategy targeting the Vmat2 gene in mice was implemented. This manipulation was sufficient to alter psychomotor behavior induced by amphetamine. The acute effect of the drug was accentuated above control levels, suggesting super-sensitivity in the drug-na ve state resembling a “pre-sensitized” phenotype. However, no progressive increase with repeated injections was observed. This study identifies a distinct TrpV1+ VTA subpopulation as a critical modulatory component in responsiveness to amphetamine. Moreover, expression of the gene encoding TRPV1 in selected VTA neurons opens up for new possibilities in pharmacolog

Published
2021
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29. Selective Knockout of the Vesicular Monoamine Transporter 2 (Vmat2) Gene in Calbindin2/Calretinin-Positive Neurons Results in Profound Changes in Behavior and Response to Drugs of Abuse

Author

König, Niclas, Bimpisidis, Zisis, Dumas, Sylvie, and Wallén-Mackenzie, Åsa

Subjects
locus coeruleus, Cognitive Neuroscience, amphetamine, ventral tegmental area, vesicular monoamine transporter (VMAT2), Neurosciences, raphe nuclei, lcsh:RC321-571, serotonin, Behavioral Neuroscience, Neuropsychology and Physiological Psychology, nervous system, substantia nigra, dopamine, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Neurovetenskaper, Original Research
Abstract

The vesicular monoamine transporter 2 (VMAT2) has a range of functions in the central nervous system, from sequestering toxins to providing conditions for the quantal release of monoaminergic neurotransmitters. Monoamine signaling regulates diverse functions from arousal to mood, movement, and motivation, and dysregulation of VMAT2 function is implicated in various neuropsychiatric diseases. While all monoamine-releasing neurons express the Vmat2 gene, only a subset is positive for the calcium-binding protein Calbindin 2 (Calb2; aka Calretinin, 29 kDa Calbindin). We recently showed that about half of the dopamine neurons in the mouse midbrain are positive for Calb2 and that Calb2 is an early developmental marker of midbrain dopamine cells. Calb2-positive neurons have also been identified in other monoaminergic areas, yet the role of Calb2-positive monoaminergic neurons is poorly understood. To selectively address the impact of Calb2-positive monoaminergic neurons in behavioral regulation, we took advantage of the Cre-LoxP system to create a new conditional knockout (cKO) mouse line in which Vmat2 expression is deleted selectively in Calb2-Cre-positive neurons. In this Vmat2(lox/lox;Calb2-Cre) cKO mouse line, gene targeting of Vmat2 was observed in several distinct monoaminergic areas. By comparing control and cKO mice in a series of behavioral tests, specific dissimilarities were identified. In particular, cKO mice were smaller than control mice and showed heightened sensitivity to the stereotypy-inducing effects of amphetamine and slight reductions in preference toward sucrose and ethanol, as well as a blunted response in the elevated plus maze test. These data uncover new knowledge about the role of genetically defined subtypes of neurons in the brain's monoaminergic systems.

Published
2020
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31. Structural and Functional Characterization of the Interaction of Snapin with the Dopamine Transporter: Differential Modulation of Psychostimulant Actions

Author

Boussicault, Lydie, Kacher, Radhia, Lamaziere, Antonin, Caboche, Jocelyne, Betuing, Sandrine, Potier, Marie-Claude, Erdozain, Amaia, de Gois, Stephanie, Bernard, Véronique, Gorgievski, Victor, Pietrancosta, Nicolas, Dumas, Sylvie, Macedo, Carlos, Vanhoutte, Peter, Ortega, Jorge, Meana, J Javier, Tzavara, Eleni, Vialou, Vincent, Giros, Bruno, Department of Pharmacology [Bizkaia, Spain], University of the Basque Country [Bizkaia] (UPV/EHU), Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders (NPS-07), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des biomolécules (LBM UMR 7203), Institut National de la Santé et de la Recherche Médicale (INSERM)-Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Mécanismes adaptatifs : des organismes aux communautés (MAOAC), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), McGill University = Université McGill [Montréal, Canada], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Neurogénétique moléculaire, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Systèmes glutamatergiques normaux et pathologiques = Normal and Pathologic Glutamatergic Neurons (NPS-05), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Chimie Moléculaire de Paris Centre (FR 2769), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Muséum national d'Histoire naturelle (MNHN)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), McGill University, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), UPV/EHU Université du Pays Basque, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Oramacell [Paris, France], École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Vanhoutte, Peter, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Systèmes glutamatergiques normaux et pathologiques = Normal and Pathologic Glutamatergic Neurons (NPS)

Subjects
Models, Molecular, 0301 basic medicine, Synaptic cleft, Dopamine Plasma Membrane Transport Proteins, Vesicular Transport Proteins, Down-Regulation, Motor Activity, Neurotransmission, Reuptake, Mice, 03 medical and health sciences, 0302 clinical medicine, Dopamine, parasitic diseases, mental disorders, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amphetamine, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Dopamine transporter, Pharmacology, Binding Sites, biology, Dopaminergic Neurons, Dopaminergic, Brain, Rats, 3. Good health, Psychiatry and Mental health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 030104 developmental biology, nervous system, biology.protein, Original Article, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, [CHIM.CHEM]Chemical Sciences/Cheminformatics, 030217 neurology & neurosurgery, Protein Binding, medicine.drug
Abstract

International audience; The importance of dopamine (DA) neurotransmission is emphasized by its direct implication in several neurological and psychiatric disorders. The DA transporter (DAT), target of psychostimulant drugs, is the key protein that regulates spatial and temporal activity of DA in the synaptic cleft via the rapid reuptake of DA into the presynaptic terminal. There is strong evidence suggesting that DAT-interacting proteins may have a role in its function and regulation. Performing a two-hybrid screening, we identified snapin, a SNARE-associated protein implicated in synaptic transmission, as a new binding partner of the carboxyl terminal of DAT. Our data show that snapin is a direct partner and regulator of DAT. First, we determined the domains required for this interaction in both proteins and characterized the DAT-snapin interface by generating a 3D model. Using different approaches, we demonstrated that (i) snapin is expressed in vivo in dopaminergic neurons along with DAT; (ii) both proteins colocalize in cultured cells and brain and, (iii) DAT and snapin are present in the same protein complex. Moreover, by functional studies we showed that snapin produces a significant decrease in DAT uptake activity. Finally, snapin downregulation in mice produces an increase in DAT levels and transport activity, hence increasing DA concentration and locomotor response to amphetamine. In conclusion, snapin/DAT interaction represents a direct link between exocytotic and reuptake mechanisms and is a potential target for DA transmission modulation.

Published
2017
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33. Developmental Co-expression of Vglut2 and Nurr1 in a Mes-Di-Encephalic Continuum Preceeds Dopamine and Glutamate Neuron Specification

Author

Dumas, Sylvie and Wallén-Mackenzie, Åsa

Subjects
Vmat2, Neurologi, Viaat, Neurosciences, glutamate, Cell Biology, subtype, Cell and Developmental Biology, Nurr1, Neurology, lcsh:Biology (General), nervous system, Vglut2, dopamine, heterogeneity, lcsh:QH301-705.5, Neurovetenskaper, Developmental Biology, Original Research
Abstract

Midbrain dopamine (DA) neurons exist as several subtypes and are found in a heterogeneous environment including GABAergic and glutamatergic neurons as well as various types of co-releasing neurons. Developmental programs underlying this heterogeneity have remained elusive. In this study, combinatorial mRNA analysis was performed at stages when neuronal phenotypes are first specified. Vesicular transporters for dopamine and other monoamines (VMAT2), GABA (VIAAT), and glutamate (VGLUT2) were assessed by systematically applying fluorescent in situ hybridization through the mes-di-encephalon of the mouse embryo at embryonal days (E) 9.5-14.5. The results show that early differentiating dopamine neurons express the gene encoding VGLUT2 before onset of any dopaminergic markers. Prior to its down-regulation in maturing dopamine neurons, Vglut2 mRNA co-localizes extensively with Tyrosine hydroxylase (Th) and Nurr1, commonly used as markers for DA neurons. Further, Vglut2 and Nurr1 mRNAs are shown to overlap substantially in diencephalic neurons that maintain a glutamatergic phenotype. The results suggest that Vglut2/Nurr1-double positive cells give rise both to dopaminergic and glutamatergic neurons within the mes-di-encephalic area. Finally, analysis of markers representing subtypes of dopamine neurons, including the newly described NeuroD6 subtype, shows that certain subtype specifications arise early. Histological findings are outlined in the context of neuroanatomical concepts and the prosomeric model of brain development. The study contributes to the current decoding of the recently discovered heterogeneity among neurons residing along the cephalic flexure.

Published
2019

34. Off-Target Effects in Transgenic Mice : Characterization of Dopamine Transporter (DAT)-Cre Transgenic Mouse Lines Exposes Multiple Non-Dopaminergic Neuronal Clusters Available for Selective Targeting within Limbic Neurocircuitry

Author

Papathanou, Maria, Dumas, Sylvie, Pettersson, Hanna, Olson, Lars, and Wallén-Mackenzie, Åsa

Subjects
nervous system, Gad1, habenula, Vglut2, Neurosciences, amygdala, mammillary, Neurovetenskaper, septum
Abstract

Transgenic mouse lines are instrumental in our attempt to understand brain function. Promoters driving transgenic expression of the gene encoding Cre recombinase are crucial to ensure selectivity in Cre-mediated targeting of floxed alleles using the Cre-Lox system. For the study of dopamine (DA) neurons, promoter sequences driving expression of the Dopamine transporter (Dat) gene are often implemented and several DAT-Cre transgenic mouse lines have been found to faithfully direct Cre activity to DA neurons. While evaluating an established DAT-Cre mouse line, reporter gene expression was unexpectedly identified in cell somas within the amygdala. To indiscriminately explore Cre activity in DAT-Cre transgenic lines, systematic whole-brain analysis of two DAT-Cre mouse lines was performed upon recombination with different types of floxed reporter alleles. Results were compared with data available from the Allen Institute for Brain Science. The results identified restricted DAT-Cre-driven reporter gene expression in cell clusters within several limbic areas, including amygdaloid and mammillary subnuclei, septum and habenula, areas classically associated with glutamatergic and GABAergic neurotransmission. While no Dat gene expression was detected, ample co-localization between DAT-Cre-driven reporter and markers for glutamatergic and GABAergic neurons was found. Upon viral injection of a fluorescent reporter into the amygdala and habenula, distinct projections from non-dopaminergic DAT-Cre neurons could be distinguished. The study demonstrates that DAT-Cre transgenic mice, beyond their usefulness in recombination of floxed alleles in DA neurons, could be implemented as tools to achieve selective targeting in restricted excitatory and inhibitory neuronal populations within the limbic neurocircuitry.

Published
2019

39. Targeting VGLUT2 in Mature Dopamine Neurons Decreases Mesoaccumbal Glutamatergic Transmission and Identifies a Role for Glutamate Co-release in Synaptic Plasticity by Increasing Baseline AMPA/NMDA Ratio

Author

Papathanou, Maria, Creed, Meaghan, Dorst, Matthijs, Bimpisidis, Zisis, Dumas, Sylvie, Pettersson, Hanna, Bellone, Camilla, Silberberg, Gilad, Lüscher, Christian, and Wallén-Mackenzie, Åsa

Subjects
Neurologi, Cognitive Neuroscience, striatum, medium spiny neurons, Neuroscience (miscellaneous), amphetamine, ventral tegmental area, Neurosciences, cocaine, Biological Sciences, Sensory Systems, Cellular and Molecular Neuroscience, substance use disorders, Neurology, Biologiska vetenskaper, addiction, Neurovetenskaper
Abstract

Expression of the Vglut2/Slc17a6 gene encoding the Vesicular glutamate transporter 2 (VGLUT2) in midbrain dopamine (DA) neurons enables these neurons to co-release glutamate in the nucleus accumbens (NAc), a feature of putative importance to drug addiction. For example, it has been shown that conditional deletion of Vglut2 gene expression within developing DA neurons in mice causes altered locomotor sensitization to addictive drugs, such as amphetamine and cocaine, in adulthood. Alterations in DA neurotransmission in the mesoaccumbal pathway has been proposed to contribute to these behavioral alterations but the underlying molecular mechanism remains largely elusive. Repeated exposure to cocaine is known to cause lasting adaptations of excitatory synaptic transmission onto medium spiny neurons (MSNs) in the NAc, but the putative contribution of VGLUT2-mediated glutamate co-release from the mesoaccumbal projection has never been investigated. In this study, we implemented a tamoxifen-inducible Cre-LoxP strategy to selectively probe VGLUT2 in mature DA neurons of adult mice. Optogenetics-coupled patch clamp analysis in the NAc demonstrated a significant reduction of glutamatergic neurotransmission, whilst behavioral analysis revealed a normal locomotor sensitization to amphetamine and cocaine. When investigating if the reduced level of glutamate co-release from DA neurons caused a detectable post-synaptic effect on MSNs, patch clamp analysis identified an enhanced baseline AMPA/NMDA ratio in DA receptor subtype 1 (DRD1)-expressing accumbal MSNs which occluded the effect of cocaine on synaptic transmission. We conclude that VGLUT2 in mature DA neurons actively contributes to glutamatergic neurotransmission in the NAc, a finding which for the first time highlights VGLUT2-mediated glutamate co-release in the complex mechanisms of synaptic plasticity in drug addiction.

Published
2018

44. The GABAergic Gudden's dorsal tegmental nucleus: A new relay for serotonergic regulation of sleep-wake behavior in the mouse.

Author

Chazalon, Marine, Dumas, Sylvie, Bernard, Jean-François, Sahly, Iman, Tronche, François, de Kerchove d'Exaerde, Alban, Hamon, Michel, Adrien, Joëlle, Fabre, Véronique, Bonnavion, Patricia, Chazalon, Marine, Dumas, Sylvie, Bernard, Jean-François, Sahly, Iman, Tronche, François, de Kerchove d'Exaerde, Alban, Hamon, Michel, Adrien, Joëlle, Fabre, Véronique, and Bonnavion, Patricia

Abstract

Serotonin (5-HT) neurons are involved in wake promotion and exert a strong inhibitory influence on rapid eye movement (REM) sleep. Such effects have been ascribed, at least in part to the action of 5-HT at post-synaptic 5-HT1A receptors (5-HT1AR) in the brainstem, a major wake/REM sleep regulatory center. However, the neuroanatomical substrate through which 5-HT1AR influence sleep remains elusive. We therefore investigated whether a brainstem structure containing a high density of 5-HT1AR mRNA, the GABAergic Gudden's dorsal tegmental nucleus (DTg), may contribute to 5-HT-mediated regulatory mechanisms of sleep-wake stages. We first found that bilateral lesions of the DTg promote wake at the expense of sleep. In addition, using local microinjections into the DTg in freely moving mice, we showed that local activation of 5-HT1AR by the prototypical agonist 8-OH-DPAT enhances wake and reduces deeply REM sleep duration. The specific involvement of 5-HT1AR in the latter effects was further demonstrated by ex vivo extracellular recordings showing that the selective 5-HT1AR antagonist WAY 100635 prevented DTg neuron inhibition by 8-OH-DPAT. We next found that GABAergic neurons of the ventral DTg exclusively targets/connects glutamatergic neurons of the lateral mammillary nucleus (LM) in the posterior hypothalamus by means of anterograde and retrograde tracing techniques using cre driver mouse lines and a modified rabies virus. Altogether, our findings strongly support the idea that 5-HT-driven enhancement of wake results from 5-HT1AR-mediated inhibition of DTg GABAergic neurons that would in turn disinhibit glutamatergic neurons in the mammillary bodies. We therefore propose a Raphe→DTg→LM pathway as a novel regulatory circuit underlying 5-HT modulation of arousal., info:eu-repo/semantics/published

Published
2018

45. Normal and pathological neuronal distribution of the human mesencephalic locomotor region

Author

Sébille, Sophie B., primary, Rolland, Anne‐Sophie, additional, Faillot, Matthieu, additional, Perez‐Garcia, Fernando, additional, Colomb‐Clerc, Antoine, additional, Lau, Brian, additional, Dumas, Sylvie, additional, Vidal, Sara Fernandez, additional, Welter, Marie‐Laure, additional, Francois, Chantal, additional, Bardinet, Eric, additional, and Karachi, Carine, additional

Published
2018
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46. Targeting VGLUT2 in Mature Dopamine Neurons Decreases Mesoaccumbal Glutamatergic Transmission and Identifies a Role for Glutamate Co-release in Synaptic Plasticity by Increasing Baseline AMPA/NMDA Ratio

Author

Papathanou, Maria, primary, Creed, Meaghan, additional, Dorst, Matthijs C., additional, Bimpisidis, Zisis, additional, Dumas, Sylvie, additional, Pettersson, Hanna, additional, Bellone, Camilla, additional, Silberberg, Gilad, additional, Lüscher, Christian, additional, and Wallén-Mackenzie, Åsa, additional

Published
2018
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50. Structural and Functional Characterization of the Interaction of Snapin with the Dopamine Transporter: Differential Modulation of Psychostimulant Actions

Author

Erdozain, Amaia M, primary, De Gois, Stéphanie, additional, Bernard, Véronique, additional, Gorgievski, Victor, additional, Pietrancosta, Nicolas, additional, Dumas, Sylvie, additional, Macedo, Carlos E, additional, Vanhoutte, Peter, additional, Ortega, Jorge E, additional, Meana, J Javier, additional, Tzavara, Eleni T, additional, Vialou, Vincent, additional, and Giros, Bruno, additional

Published
2017
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