Institut du Fer à Moulin

IFM

Girault

Neurotransmission and signaling

Our goal is to identify intracellular signaling mechanisms that underlie brain plasticity leading to long-lasting behavioral alterations.

Scientific context

The ability of the nervous system to adapt to a variable environment and to learn depends on the modulation and plasticity of synapses between neurons, which is regulated by their activity and by multiple neuromodulators. Long-lasting modifications also include more general morphological and functional alterations, and involve variations in protein translation and gene transcription.

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 striatal projection neurons (SPNs) are GABAergic also known as medium-size spiny neurons (MSNs). They 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 extracellular dopamine in the striatum.
Dopamine-activated signaling is also responsible for therapeutic and side effects (dyskinesia) of L-DOPA in Parkinson’s 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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Some actions of dopamine on striatal neurons. In neurons that express D1 receptors (Drd1), their stimulation activates adenylyl cyclase 5 (Adcy5, AC-V) through the heterotrimeric G protein G(alpha)olf (Gnal). cAMP effects include activation of cAMP-dependent protein kinase (PKA). In neurons that express D2 receptors (Drd2), they inhibit cAMP production which is stimulated by other transmitters, including adenosine acting on A2a receptors (Adora2a).

Previous results

Our lab contributed to the identification of signaling pathways activated by dopamine and other neurotransmitters. They involve G(alpha)olf, cAMP-dependent protein kinase (PKA), extracellular signal-regulated kinase (ERK), as well as regulation of protein phosphatases, such as that achieved by dopamine- and cAMP-regulated phosphoprotein (DARPP-32), an inhibitor of protein phosphatase-1. We identified some of their functionally relevant targets, including in the nucleus. We also showed the multiple signaling differences between neurons which express D1 or D2 receptors. These mechanisms, contribute to the long-lasting behavioral responses to drugs of abuse and the appearance of L-DOPA-induced dyskinesia and the effects of antipsychotic drugs.

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Selective activation ERK in the striatal neurons that express D1 receptors following cocaine injection in mice. Activated ERK is detected by immunofluorescence (red). Left panel, D1 neurons express enhanced green fluorescent protein (EGFP). Right panel, D2 neurons express EGFP. Bertran-Gonzalez et al., J. Neurosci, 2008.

Our lab also investigated other aspects of signaling in neurons including the role and regulation of non-receptor tyrosine kinases FAK (focal adhesion kinase) and Pyk2. We clarified the molecular mechanisms of FAK activation and of Pyk2 cytonuclear shuttling. Our recent results provide evidence for the role of Pyk2 in the function and plasticity of hippocampal synapses and its involvement in various pathological conditions including Huntington’s and ALzheimer’s diseases and the effects of chronic stress.

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Three-D model of dimeric FAK based on SAXS (small angle X-ray scattering) data. Brami-Cherrier et al. EMBO J, 2014. (collab. S. Arold)

Ongoing work and projects

  • Study of signaling pathways from synapses to nucleus and their functional consequences.
  • Characterization of transcriptional and epigenetic alterations induced by psychostimulants or operant conditioning in identified neuronal populations of the striatum.
  • Links between striatal signaling and movement disorders, focalizing on Gnal and Adcy5.
  • Mechanisms of activation and function of Pyk2 in neurons.
  • Role of Pyk2 in models of Huntington’s and Alzheimer’s disease.

Group leader : Jean-Antoine Girault, MD, PhD (Inserm Research Director, DRCE)

  • Denis Hervé, PhD, Inserm research Director, DR2
  • Gress Kadaré, PhD, Lecturer, Sorbonne Université
  • Sophie Longueville, AI Inserm
  • Tiago Mendes, PhD, Post-doc
  • Louise-Laure Mariani, MD, PhD, Neurologist researcher
  • Ruiyi Yuan, PhD student, Sorbonne Université

Former team members :

  • Cristina Alcácer Fernández-Coronado, Champalimaud Institute, Lisbon, Portugal
  • Omar al Massadi, University of Santiago de Compostela, Espagne
  • Karen Brami-Cherrier, University of California at Irvine, USA
  • Damien Carrel, Lecturer, Paris University
  • Jean-Christophe Corvol, ICM, Paris
  • Renata Coura, Paris
  • Benoit de Pins, Weizmann Institute , Rehovot, Israël
  • Olivia Engmann, Universitätsklinikum Jena, Allemagne
  • Camille Faure, CNRS scientist, Cochin Institute, Paris
  • Nicolas Gervasi, Inserm, Collège de France
  • Albert Giralt, University of Barcelona, Spain
  • Lucile Marion-Poll, Geneva University
  • Vincenzo Mastrolia, London, UK
  • Enrica Montalban, CNRS UMR 8251, Paris University
  • Yukari Nakamura, Kurume University, Japan
  • Yuki Nakamura, Kurume University, Japan
  • Assunta Pelosi, Institut Pasteur, Paris

Main collaborations in France

  • Jocelyne Caboche, Peter Vanhoutte, Sandrine Betuing, CNRS, Inserm, Sorbonne University, IBPS, Paris
  • Jacques Hugon, Inserm Lariboisière, Paris
  • Emmanuel Rozes, ICM, Paris
  • Emmanuel Valjent, IGF, Inserm, CNRS Montpellier

Main international collaborations

  • Stefan Arold, KAUST, Saudi Arabia
  • Albert Giralt, Université de Barcelone
  • Angus C. Nairn, Yale University, New Haven, CT, USA
  • Akinori Nishi, Kurume University School of Medicine, Kurume, Fukuoka, Japan
  • Jean-Pierre Roussarie, Rockefeller University, New York

Current funding

The lab is supported by Inserm, Sorbonne Université, Agence Nationale de la Recherche (ANR), Fondation pour la recherche médicale (FRM) and Fondation de France.

Most recent Publications

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration.

Hirose T, Cabrera-Socorro A, Chitayat D, Lemonnier T, Féraud O, Cifuentes-Diaz C, Gervasi N, Mombereau C, Ghosh T, Stoica L, Bacha JDA, Yamada H, Lauterbach MA, Guillon M, Kaneko K, Norris JW, Siriwardena K, Blasér S, Teillon J, Mendoza-Londono R, Russeau M, Hadoux J, Ito S, Corvol P, Matheus MG, Holden KR, Takei K, Emiliani V, Bennaceur-Griscelli A, Schwartz CE, Nguyen G, Groszer M.

J Clin Invest. 2019 Apr 15;129(5):2145-2162.

PMID:30985297

All Team Girault's Publications

Selection of recent publications

 

A few reviews…

  • de Pins B, Mendes T, Giralt A, Girault JA. The non-receptor tyrosine kinase Pyk2 in brain function and neurological and psychiatric diseases. Front Synaptic Neurosci. 2021, 13:749001.
  • Girault JA, Nairn AC. DARPP-32 40 years later. Adv Pharmacol. 2021 90:67-87.
  • Girault JA. Epigenetic tinkering with neurotransmitters. (Perspective) Science, 2020, 368:134-5.
  • Al-Massadi O, Dieguez C, Nogueiras R, Girault JA. Ghrelin and food reward. Neuropharmacology, 2019, 148:131-8.
  • Walkiewicz KW, Girault JA, Arold ST. How to awaken your nanomachines: Site-specific activation of focal adhesion kinases through ligand interactions. Prog Biophys Mol Biol, 2015, 119:60-71.
  • Girault JA. Integrating neurotransmission in striatal medium spiny neurons. Adv Exp Med Biol, 2012, 970:407-29.
  • Girault JA. Signaling in striatal neurons: the phosphoproteins of reward, addiction, and dyskinesia. Prog Mol Biol Transl Sci, 2012, 106:33-62.
  • Yger M, Girault JA. DARPP-32, jack of all trades…master of which? Front Behav Neurosci, 2011, 5:56.