Neurotransmission and signaling
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 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).
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.
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.
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
- Yuki Nakamura, MD, PhD, Post-doc
- Louise-Laure Mariani, MD, PhD, Neurologist researcher
- Yukari Nakamura MD, PhD student, Kurume University
- 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 scientist, Collège de France
- Albert Giralt, University of Barcelona, Spain
- Lucile Marion-Poll, EMBL
- Vincenzo Mastrolia, London, UK
- Enrica Montalban, CNRS UMR 8251, Paris University
- Assunta Pelosi, Sanofi-Aventis
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
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
Puighermanal E, Castell L, Esteve-Codina A, Melser S, Kaganovsky K, Zussy C, Boubaker-Vitre J, Gut M, Rialle S, Kellendonk C, Sanz E, Quintana A, Marsicano G, Martin M, Rubinstein M, Girault JA, Ding JB, Valjent E.
Nat Commun. 2020 Apr 23;11(1):1957.
de Pins B, Montalban E, Vanhoutte P, Giralt A, Girault JA.
Sci Rep. 2020 Apr 20;10(1):6619.
Science. 2020 Apr 10;368(6487):134-135.
Mariani LL, Longueville S, Girault JA, Hervé D, Gervasi N.
Neurobiol Dis. 2019 Oct;130:104506.
Brito V, Giralt A, Masana M, Royes A, Espina M, Sieiro E, Alberch J, Castañé A, Girault JA, Ginés S.
Biol Psychiatry. 2019 Aug 1;86(3):196-207.
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.
Tible M, Mouton Liger F, Schmitt J, Giralt A, Farid K, Thomasseau S, Gourmaud S, Paquet C, Rondi Reig L, Meurs E, Girault JA, Hugon J.
Aging Cell. 2019 Jun;18(3):e12887.
Etienne F, Mastrolia V, Maroteaux L, Girault JA, Gervasi N, Roumier A.
J Vis Exp. 2019 Jan 31;(143).
de Pins B, Cifuentes-Díaz C, Farah AT, López-Molina L, Montalban E, Sancho-Balsells A, López A, Ginés S, Delgado-García JM, Alberch J, Gruart A, Girault JA, Giralt A.
J Neurosci. 2019 Mar 27;39(13):2441-2458.
Montalban E, Al-Massadi O, Sancho-Balsells A, Brito V, de Pins B, Alberch J, Ginés S, Girault JA, Giralt A.
Transl Psychiatry. 2019 Jan 15;9(1):3.
Selection of recent publications
- de Pins B, Montalban E, Vanhoutte P, Giralt A, Girault JA. The non-receptor tyrosine kinase Pyk2 modulates acute locomotor effects of cocaine in D1 receptor-expressing neurons of the nucleus accumbens. Sci Rep, 2020, in press.
- Puighermanal E, Castell L, Esteve A, Melser S, Kaganovsky K, Zussy C, Boubaker-Vitre J, Gut M, Rialle S, Kellendonk C, Sanz E, Quintana A, Marsicano G, Martin M, Rubinstein M, Girault JA, Ding JB, Valjent E. Translatome study of dopamine D2 receptors-expressing striatal neurons identifies a population of Wfs1 neurons that control specific motor behaviors. Nat Commun, 2020, in press.
- Brito V, Giralt A, Masana M, Royes A, Espina M, Sieiro E, Alberch J, Castañe A, Girault JA, Ginés S. Cdk5 dysfunction contributes to depressive-like behaviors in Huntington´s Disease by altering the phospho-DARPP-32 status in the nucleus accumbens. Biol Psychiatry, 2019, 86:196-207.
- Tible M, Mouton-Liger F, Schmitt J, Giralt A, Farid K, Thomasseau S, Gourmaud S, Paquet C, Rondi Reig L, Meurs E, Girault JA, Hugon J. PKR knockout in the 5XFAD model of Alzheimer’s disease reveals beneficial effects on spatial memory and brain lesions. Aging Cell, 2019, 18(3) 1:e12887.
- Mariani LL, Longueville S, Girault JA, Hervé D, Gervasi N. Differential enhancement of ERK, PKA and Ca2+ signaling in direct and indirect striatal neurons of Parkinsonian mice. Neurobiol Dis, 2019 130:104506.
- de Pins B, Cifuentes-Díaz C, Farah A, López-Molina L, Montalban E, Sancho-Balsells A, Lopez A, Gines S, Delgado-García JM, Alberch J, Gruart A, Girault JA, Giralt A. Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease. J Neurosci, 2019 39:2441-58.
- Montalban E, Al Massadi O, Sancho-Balsells A, Brito V, de Pins B, Alberch J, Ginés S, Girault JA, Giralt A. Pyk2 in the amygdala modulates chronic stress sequelae via PSD-95-related micro-structural changes. Trans Psychiatr, 2019, 9(1)3.
- Marion-Poll L, Besnard A, Longueville S, Valjent E, Engmann O, Caboche J, Hervé D, Girault JA. Cocaine conditioned place preference: unexpected suppression of preference due to testing combined with strong conditioning conditions. Addict Biol, 2019, 24:364-75.
- Giralt A, de Pins B, Cifuentes-Díaz C, Lopez-Molina L, Thamila Farah A, Tible M, Deramecourt V, Arold S, Ginés S, Hugon J, Girault JA. PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer’s disease. Exp Neurol, 2018, 307:62-73.
- Pelosi A, Menardy F, Popa D, Girault JA, Hervé D. Heterozygous Gnal mice are a novel animal model to study dystonia pathophysiology neurons. J Neurosci, 2017, 37: 6253-67.
- Giralt A, Brito V, Chevy Q, Simonnet C, Otsu Y, Cifuentes-Díaz C, de Pins B, Coura R, Alberch J, Ginés S, Poncer JC, Girault JA. Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington’s disease model. Nat Commun, 2017, 8:15592.
- Giralt A, Coura R, Girault JA. Pyk2 is essential for astrocytes mobility following brain lesion. Glia, 2016, 64:620-34.
- 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, 21:1545-1553.
- Li L, Gervasi N, Girault JA. Dendritic geometry shapes neuronal cAMP signaling to the nucleus. Nat Commun, 2015, 6:6319.
- 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. Nat Commun, 2015, 6:10099.
A few reviews…
- 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.