Team 1 : Neurotransmission and signaling (Girault / Hervé)

Team leaders : Jean-Antoine Girault (Inserm Research Director, DRE) and Denis Hervé (Inserm research Director, DR2)

Team 1 includes the group of Denis Hervé and Jean-Antoine Girault who study signal transduction in neurons and the group of Laurence Goutebroze who is interested in axo-glial interactions in myelinated fibers.

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Our goal is to identify intracellular signaling mechanisms that underlie brain plasticity leading to long-lasting behavioral alterations.
The ability of the nervous system to adapt to a variable environment depends on the modulation and plasticity of synapses between these neurons, which is regulated by their activity and by multiple neuromodulators.
Intracellular signaling pathways are essential for these adaptations and involve chemical reactions among which protein phosphorylation plays a central role. Hence, our group studies protein kinases (which add phosphoryl groups to proteins) and protein phosphatases (which remove phosphoryl groups).

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Our major model of study is the striatum, which plays a crucial role in the control of movements, motivation , formation of habits, and procedural memory, and is involved in major neurological and psychiatric conditions.

The striatum is the "entry" structure of the basal ganglia, a set of complex neuronal loops thought to be responsible for action selection.
The principal neurons of the striatum are GABAergic medium-size spiny neurons (MSNs), which integrate sensorimotor information provided by glutamate inputs from the cerebral cortex and thalamus, with a reward prediction error value provided by dopamine afferents.
Dopamine controls both the acute function of basal ganglia circuits and their long-lasting plasticity, which contributes to reinforcement learning. Drugs of abuse divert these processes by directly increasing dopamine transmission.
Dopamine-activated signaling is also responsible for therapeutic and side effects (dyskinesia) of L-DOPA in Parkinson disease. In addition, it is involved in the effects of antipsychotic agents, and may be altered in conditions such as obsessive-compulsive disorder(OCD) and attention deficit and hyperactivity disorder(ADHD).

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Our previous work contributed to the identification of signaling pathways activated by glutamate NMDA and dopamine D1 receptors, G(alpha)olf, cAMP-dependent protein kinase (PKA), extracellular signal-regulated kinase (ERK) in striatonigral neurons. In mature striatum, these pathways require dopamine- and cAMP-regulated phosphoprotein (DARPP-32), an inhibitor of protein phosphatase-1. We identified some of their functionally relevant targets, including the regulation of nucleosomal response and the transcription of immediate-early genes such as Zif268/Krox24/Egr1. These mechanisms, which contribute to the long-lasting behavioral responses to drugs of abuse and the appearance of L-DOPA-induced dyskinesia, are modulated by many other intercellular messengers including the endocannabinoid system.

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We have also investigated other aspects of signaling in neurons including the role and regulation of non-receptor tyrosine kinases, including FAK (focal adhesion kinase), PYK2 and the associated Src-family kinases.

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Our general aim is to decipher the signaling pathways normally activated in the striatum by reinforcement learning and leading to long-lasting behavioral changes. We try to identify their dysregulation in response to drugs of abuse, and to L-DOPA in models of Parkinson disease.
We study the molecular properties of signaling enzymes and the mechanism of information transfer from the cytoplasm to the nucleus.
We use a combination of experimental approaches from biochemistry and molecular genetics to behavior and functional anatomy.
Our research helps to understand the pathological mechanisms of diseases involving the basal ganglia, including Parkinson disease and drug addiction. It also aims at identifying new therapeutic strategies for these diseases and understanding the therapeutic and side effects of L-DOPA and antipsychotic drugs. This research has also more general implications, especially in the field of cancer because the signaling pathways we study control many other cellular functions.

Team leaders : Jean-Antoine Girault (Inserm Research Director, DRE) & Denis Hervé (Inserm research Director, DR2)

  • Nicolas Gervasi, CR2 Inserm
  • Gress Kadaré, MCU UPMC
  • Sophie Longueville, AI INSERM
  • Lieng Taing, IR (CDD)
  • Assunta Pelosi, Post-doc
  • Albert Giralt, Post-doc
  • Enrica Montalban, Post-doc
  • Yuki Nakamura, Post-doc
  • Louise-Laure Mariani, PhD student UPMC
  • Yukari Nakamura, PhD student
  • Benoît de Pins, PhD student UPMC

Former team members :

  • Cristina Alcácer Fernández-Coronado, Post-doc, Lund University, Sweden 
  • Karen Brami-Cherrier, Post-doc, University of California at Irvine, USA
  • Damien Carrel, MCU Paris-Descartes
  • Renata Coura, Post-doc
  • Olivia Engmann, Post-doc USA
  • Camille Faure, Post-doc, Institut Cochin
  • Emmanuelle Jordi, Paris, Bio-Tech
  • Lucile Marion-Poll, Post-doc
  • Matthieu Maroteaux, Post-doc, New Orleans, USA
  • Vincent Pascoli, Post-doc, University of Geneva, Switzerland
  • Marie-Josèphe Salles, Paris

Main collaborations in France :

  • Jocelyne Caboche, CNRS and UPMC UMR 7102, Paris
  • Emmanuel Valjent, IGF, Montpellier
  • Pierre Vincent & Danièle Tritsch, UMR-7102 CNRS, UPMC, Jussieu, Paris

Main international collaborations

  • Ted Abel, University of Iowa, USA
  • Stefan Arold,KAUST, Saudi Arabia
  • Avrama Blackwell, George Mason University, USA
  • Paul Greengard, The Rockefeller University, New York NY, USA
  • Angus C. Nairn, Yale University, New Haven CT, USA
  • Akinori Nishi, Kurume University School of Medicine, Kurume, Fukuoka, Japan
  • Nicolas Le Novère, Babraham Institute, Cambridge, UK

Publications

2016

De Bundel D, Zussy C, Espallergues J,  Gerfen CR, Girault JA, Valjent E. Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala. Mol Psy, 2016, 21:1545-53.

Engmann O, Giralt A, Girault JA. Acute drug-induced spine changes in the nucleus accumbens are dependent on b-adducin. Neuropharmacology, 2016, 110:333-42.

Giralt A, Coura R, Girault JA. Pyk2 is essential for astrocytes mobility following brain lesion. Glia, 2016, 64:620-34.

Lecca S, Pelosi A, Tchenio A, Moutkine I, Lujan R, Hervé D, Mameli M. Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice. Nat Med. 2016, 22:254-61.

Luczak V, Blackwell KT, Abel T, Girault JA, Gervasi N. Dendritic diameter influences the rate and magnitude of hippocampal cAMP and PKA transients during β-adrenergic receptor activation. Neurobiol Learn Mem. 2016 Aug 11. pii: S1074-7427(16)30149-6. [Epub ahead of print]

Martin PM, Cifuentes-Diaz C, Devaux J, Garcia M, Bureau J, Thomasseau S, Klingler E, Girault JA, Goutebroze L. Schwannomin-interacting protein 1 isoform IQCJ-SCHIP1 is a multi-partner ankyrin and spectrin binding protein involved in the organization of nodes of Ranvier. J Biol Chem, 2016 Dec 15. pii: jbc.M116.758029. [Epub ahead of print]

Nishi A, Matamales M, Musante V, Valjent E, Kuroiwa M, Kitahara Y, Rebholz H, Greengard P, Girault JA, Nairn AC. Glutamate counteracts dopamine/PKA signaling via dephosphorylation of DARPP-32 Ser97 and alteration of its cytonuclear distribution. J Biol Chem, 2016 Dec. [Epub ahead of print]

Puighermanal E, Cutando L, Boubaker-Vitre J, Honoré E, Longueville S, Hervé D, Valjent E. Anatomical and molecular characterization of dopamine D1 receptor-expressing neurons of the mouse CA1 dorsal hippocampus. Brain Struct Funct. 2016 Sep 27. [Epub ahead of print]

Stacey D, Lourdusamy A, Ruggeri B, Maroteaux M, Jia T, Cattrell A, Nymberg C, Banaschewski T, Bhattacharyya S, Band H, Barker G, Bokde A, Buchel C, Carvalho F, Conrod P, Desrivieres S, Easton A, Fauth-Buehler M, Fernandez-Medarde A, Flor H, Frouin V, Gallinat J, Garavanh H, Heinz A, Ittermann B, Lathrop M, Lawrence C, Loth E, Mann K, Martinot JL, Nees F, Paus T, Pausova Z, Rietschel M, Rotter A, Santos E, Smolka M, Sommer W, Mameli M, Spanagel R, Girault JA, Mueller C, Schumann G; IMAGEN consortium. A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males. J Psychiatry Neurosci. 2016 41:192-202.

2015

Biever A, Puighermanal E, Nishi A, David A, Panciatici C, Longueville S, Xirodimas D, Gangarossa G, Meyuhas O, Hervé D, Girault JA, Valjent E. PKA-dependent phosphorylation of ribosomal protein S6 does not correlate with translation efficiency in striatonigral and striatopallidal medium-sized spiny neurons. J Neurosci 2015, 35:4113-30COVER ILLUSTRATION.

Charbonnier-Beaupel F*, Malerbi M*, Alcacer C*, Tahiri K, Carpentier W, Wang C, During M, Xu D, Worley P, Girault JA, Hervé D, Corvol JC. *equal contribution. Gene expression analyses identify Narp contribution in the development of L-DOPA-induced dyskinesia. J Neurosci,2015, 35:96-111.

Engmann O, Giralt A*, Gervasi N*, Marion-Poll L, Gasmi L, Filhol O, Picciotto MR, Gilligan D, Greengard P, Nairn AC, Hervé D, Girault JA. DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons. Nature Comm, 2015, Dec 7;6:10099. doi: 10.1038/ncomms10099.

Kadaré G, Gervasi N, Brami-Cherrier K,  Blockus H, El Messari S, Arold S, Girault JA. Conformational dynamics of the focal adhesion targeting domain control specific functions of focal adhesion kinase in cells. J Biol Chem, 2015, 290:478-91.

Klingler E, Martin PM, Garcia M, Moreau-Fauvarque C, Falk J, Chareyre F, Giovannini M, Chedotal A, Girault JA, Goutebroze L. The cytoskeleton-associated protein SCHIP-1 is involved in axon guidance and required for piriform cortex and anterior commissure development. Development, 2015, 42:2026-36.

Kolodziejczak M, Béchade C, Gervasi N, Irinopoulou T, Banas SM, Cordier C, Rebsam A, Roumier A, Maroteaux L. Serotonin Modulates Developmental Microglia via 5-HT2B Receptors: Potential Implication during Synaptic Refinement of Retinogeniculate Projections. ACS Chem Neurosci. 2015, 6:1219-30.

Li L*, Gervasi N*, Girault JA.  Dendritic geometry shapes neuronal cAMP signaling to the nucleus. Nature Comm, 2015, 6:6319.

Meye FJ, Valentinova K, Lecca S, Marion-Poll L, Maroteaux MJ, Musardo S, Moutkine I, Gardoni F, Huganir RL, Georges F, Mameli M. Cocaine-evoked negative symptoms require AMPA receptor trafficking in the lateral habenula. Nat Neurosci. 2015, 18:376-8.

Pelosi A, Girault JA, Hervé D. Unilateral lesion of dopamine neurons induces grooming asymmetry in the mouse. PLoS-One, 2015, 10(9):e0137185. doi: 10.1371.

Polito M, Guiot E, Gangarossa G, Longueville S, Doulazmi M, Valjent E, Hervé D, Girault JA, Paupardin-Tritsch D, Castro LRV, Vincent P. Selective effects of PDE10A inhibitors on striatopallidal neurons require phosphatase inhibition by DARPP-32. e-Neuro, 2015, 2(4) e0060-15.2015 1–15.

Ruiz-DeDiego I, Naranjo JR, Hervé D, Moratalla R. Dopaminergic regulation of olfactory type G-protein α subunit expression in the striatum. Mov Disord. 2015, 30:1039-49.

2014

Alcacer C, Charbonnier-Beaupel F, Corvol JC, Girault JA, Hervé D. Mitogen- and stress-activated protein kinase 1 is required for specific signaling responses in dopamine-denervated mouse striatum, but isnot necessary for l-DOPA-induced dyskinesia. Neurosci Let 2014, 583:76–80.

Brami-Cherrier K, Gervasi N, Arsenieva D, Walkiewicz K, Boutterin MC, Ortega A, Leonard PG, Seantier B, Gasmi L, Bouceba T, Kadaré G, Girault JA*, Arold S*.  *equal contribution Dimerization controls activation of kinase-dependent functions of FAK at focal adhesions. EMBO J, 2014, 33:356-7.

Marion-Poll L, Montalban E, Munier A, Girault JA. Fluorescence-activated sorting of fixed nuclei (FAST-FIN): A general method to study nuclei from specific cell populations that preserves post-translational modifications. Eur J Neurosci, 2014, 39:1234-44.

Sánchez N*, Coura R*, Engmann O, Marion-Poll L, Longueville S, Hervé D, Andrés ME*, Girault JA*. Haloperidol-induced Nur77 expression in striatopallidal neurons is under the control of protein phosphatase 1 regulation by DARPP-32. Neuropharmacology, 2014, 79 :559-66.

2013

Bonito Oliva A, Pallottino S, Bertran-Gonzalez J, Girault JA, Valjent E, Fisone G. Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. Neuropharmacology, 2013, 72:197-203.

Boutterin MC, Mazot P, Faure C, Doly S, Gervasi N, Tremblay ML, Vigny M. Control of ALK (wild type and mutated forms) phosphorylation: specific role of the phosphatase PTP1B. Cell Signal. 2013, 25:1505-13.

Castro LRV, Brito M, Guiot E, Polito M, Korn CW, Hervé D, Girault JA, Paupardin-Tritsch D, Vincent P. Striatal neurones have a specific ability to respond to phasic dopamine release. J Physiol (London), 2013, 591:3197-214.

Faure C, Ramos M, Girault JA. Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation. Cell Mol Life Sci, 2013 70:137-52.

Fuchs T, Saunders-Pullman R, Masuho I, Luciano MS, Raymond D, Factor S, Lang AE, Liang TW, Trosch RM, White S, Ainehsazan E, Hervé D, Sharma N, Ehrlich ME, Martemyanov KA, Bressman SB, Ozelius LJ. Mutations in GNAL cause primary torsion dystonia. Nat Genet. 2013, 45:88-92.

Gangarossa G,  Espallergues J, Mailly P, De Bundel D, Marion-Poll L, de Kerchove d’Exaerde A, Hervé D, Girault JA, Valjent E, Krieger P. Spatial distribution of D1R- and D2R-expressing medium-sized spiny neurons differs along the rostro-caudal axis of the mouse dorsal striatum. Front Neural Circuits, 2013, 7:124.

Gangarossa G, Espallergues J, de Kerchove d'Exaerde A, El Mestikawy S, Gerfen CR, Hervé D, Girault JA, Valjent E. Distribution and compartmental organization of GABAergic medium-sized spiny neurons in the mouse nucleus accumbens. Front Neural Circuits, 2013 7:22.

Jordi E, Heiman M, Marion-Poll L, Guermonprez P, Cheng SK, Nairn AC, Greengard P, Girault JA. Differential effects of cocaine on histone post-translational modifications in identified populations of striatal neurons. Proc Natl Acad Sci USA. 2013, 110:9511-6.

Maroteaux M, Valjent , Longueville S, Topilko P, Girault JA, Hervé D. Role of the plasticity-associated transcription factor Zif268 in the early phase of instrumental learning. PLoS One, 2013, 9:(e81868)1-13.

Molet J, Hervé D, Thiébot MH, Hamon M, Lanfumey L. Juvenile ethanol exposure increases rewarding properties of cocaine and morphine in adult DBA/2J mice. Eur Neuropsychopharmacol. 2013, 23:1816-25.

Salles MJ, Hervé D, Rivet JM,Longueville S, Millan MJ, Girault JA, Mannoury la Cour C. Transient and rapid activation of Akt/GSK-3b and mTORC1 signaling by D3 dopamine receptor stimulation in dorsal striatum and nucleus accumbens. J Neurochem, 2013 125:532-44.

2012

Alcacer C, Santini E, Valjent E, Gaven F, Girault JA, Hervé D. Gaolf mutation allows parsing the role of cAMP- and extracellular signal-regulated kinase-dependent signaling in L-DOPA-induced dyskinesia. J Neurosci 2012, 32:5900-10.

Despeaux M, Chicanne G, Rouer E, De Toni-Costes F, Bertrand J, Mansat-De Mas V, Vergnolle V, Eaves C, Payrastre B, Girault JA, Racaud-Sultan C. Focal adhesion kinase splice variants maintain primitive acute myeloid leukemia cells through altered Wnt signaling. Stem Cells 2012, 30:1597-610.

Gangarossa G, Longueville S, De Bundel D, Perroy J, Hervé D, Girault JA, Valjent E. Characterization of Drd1a- and Drd2-expressing neurons in the mouse hippocampus. Hippocampus, 2012 22:2199-207COVER ILLUSTRATION.

Meffre J, Chaumont-Dubel S, Mannoury la Cour C, Loiseau F, Watson DJ, Dekeyne A, Séveno M, Rivet JM, Gaven F, Déléris P, Hervé D, Fone KC, Bockaert J, Millan MJ, Marin P. 5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia. EMBO Mol Med. 2012, 4:1043-56.

Stacey D*, Bilbao A*, Maroteaux M*, Jia T, Easton AC, Longueville S, Nymberg C, Banaschewski T, Barker GJ, Büchel C, Carvalho F, Conrod PJ, Desrivières S, Fauth-Bühler M, Fernandez-Medarde A, Flor H, Gallinat J, Garavan H, Bokde AL, Heinz A, Ittermann B, Lathrop M, Lawrence C, Loth E, Lourdusamy A, Mann KF, Martinot JL, Nees F, Palkovits M, Paus T, Pausova Z, Rietschel M, Ruggeri B, Santos E, Smolka MN, Staehlin O, Jarvelin MR, Elliott P, Sommer WH, Mameli M, Müller CP, Spanagel R, Girault JA*, Schumann G*, the IMAGEN Consortium. *equal contribution RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release. Proc Natl Acad Sci USA. 2012 109:21128-33.

Tourino C, Valjent E, Ruiz-Medina J, Herve D, Ledent C, Valverde O. The orphan receptor GPR3 modulates the early phases of cocaine reinforcement. Br J Pharmacol. 2012, 167:892-904.