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Developmental Brain Physiology and Pathology

Team Leader : Laurent GROC

Laurent GROC is Exceptional Class Research Director (DRCE CNRS) at the CNRS and Université de Bordeaux, head of the Team Developmental Brain Physiology and Pathology, and deputy director of the Interdisciplinary Institute for Neuroscience. His research focuses on the cellular and molecular mechanisms underlying the maturation of glutamate synapses in physiology and neuropsychiatric conditions, such as psychosis. He received his Ph.D. in Neurosciences in 2000 from Wayne State University (Michigan, USA) and Université de Lyon (France). He then joined the Department of Physiology at the University of Goteborg (Sweden) as a postdoctoral fellow to investigate the physiology of developing synapses. In 2004, he was appointed CNRS young investigator (CR) in Bordeaux to decrypt how excitatory synapses mature using an original combination of approaches. He received several prestigious awards, including the 2008 CNRS Young Investigator Award, 2009 Young Investigator Biology Award of the French Science Academy, 2015 Prix Foulon of the French Science Academy, 2015 Prix Dassault, 2016 Human Frontier Science Program Award, 2020 ERC Synergy Award, and 2022 CNRS Silver Medal. In 2020, he has been nominated Guest Professor at the Sahlgrenska Academy in Sweden. Biosketch.

General objective

Our aim is to uncover the cellular and molecular mechanisms underlying the maturation of glutamatergic synapses and brain cell networks in a physiological condition as well as in models of neuropsychiatric disorders, such as psychosis. We focus our attention on the interplay between neurotransmitter (glutamatergic, GABAergic and monoaminergic) and immune systems.As an example, we dissect how autoantibodies directed against neurotransmitter receptors and purified from patients with neuropsychiatric symptoms alter synaptic, network and behavioural functions. Finally, we explore how the extracellular space (ECS) of the brain shape cell communication and protein dynamics throughout the nervous system. To tackle these challenges, we develop and use different approaches, such as single molecule imaging in brain tissue, super-resolution imaging, FRET-FLIM, molecular biology, biochemistry, electrophysiology, and behavioural tests.

Research Projects

Autoimmunity in neuropsychiatric disorders: molecular, cellular and behavioural exploration

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Glutamate - Dopamine receptor interplay: from physiology to brain disorders

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Psychotomimetic drugs: molecular, cellular and behavioural mechanisms of action

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Immunoglobulin dynamics in the brain

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Maturation of the NMDA receptor trafficking: molecular and cell type determinants in health and psychiatric diseases

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Immun'Optic Screening Platform

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Expertise

  • Single nanoparticle tracking
  • Electrophysiology
  • Biochemistry and protein engineering
  • Super-resolution microscopy
  • News

    Retrovirus, inflammation and psychosis: a missing link identified!

    Human endogenous retroviral protein triggers deficit in glutamate synapse maturation and behaviors associated with psychosis 

    Mobile genetic elements, such as human endogenous retroviruses (HERVs), produce proteins that regulate brain cell functions and synaptic transmission and have been implicated in the etiology of neurological and neurodevelopmental psychiatric disorders. However, the mechanisms by which these proteins of retroviral origin alter brain cell communication remain poorly understood. Here, we combined single-molecule tracking, calcium imaging, and behavioral approaches to demonstrate that the envelope protein (Env) of HERV type W, which is normally silenced but expressed in patients with neuropsychiatric conditions, alters the N-methyl-d-aspartate receptor (NMDAR)–mediated synaptic organization and plasticity through glia- and cytokine-dependent changes. Env expression in the developing hippocampus was sufficient to induce behavioral impairments at the adult stage that were prevented by Env neutralization or tuning of NMDAR trafficking. Thus, we show that a HERV gene product alters glutamate synapse maturation and generates behavioral deficits, further supporting the possible etiological interplay between genetic, immune, and synaptic factors in psychosis.

    Authors: E.M. Johansson, D. Bouchet, R. Tamouza, P. Ellul, AS. Morr, E. Avignone, R. Germi, M. Leboyer, H. Perron and L. Groc

    - Science Advances 17 Jul 2020: Vol. 6, no. 29, eabc0708 - DOI: 10.1126/sciadv.abc0708
    - Contacts: Emily M. Johannson and Laurent Groc
    + More details on the Neurocampus website here

    NMDA receptor functions in health and disease: Old actor, new dimensions, Neuron - May 23

    Julien P. Dupuis, Olivier Nicole, Laurent Groc

    Neuron. 2023-05-25

    DOI: https://doi.org/10.1016/j.neuron.2023.05.002

    Summary
    The NMDA ionotropic glutamate receptor (NMDAR) plays key roles in synaptogenesis, synaptic maturation, long-term plasticity, neuronal network activity, and cognition. Mirroring this wide range of instrumental functions, abnormalities in NMDAR-mediated signaling have been associated with numerous neurological diseases and psychiatric disorders, such as schizophrenia. Thus, identifying the molecular mechanisms underpinning the physiological and pathological contributions of NMDAR has been a major area of investigation. Over the past decades, a large body of literature has flourished, revealing that the physiology of the NMDAR cannot be restricted to fluxing ions, and involves additional facets controlling synaptic transmissions in health and disease. Here, we discuss in-depth newly discovered dimensions of postsynaptic NMDAR signaling supporting neuronal plasticity and cognition, such as the nanoscale organization of NMDAR complexes, their activity-dependent redistributions, and non-ionotropic signaling capacities. Furthermore, we discuss how dysregulations of these processes may directly contribute to NMDAR-dysfunction-related brain diseases, opening new avenues for innovative therapeutical strategies.

    The PHRC TiM-DepisT project

    The PHRC TiM-DepisT project is a national hospital-based clinical research project. Its aim is to detect (DepisT) and treat (TiM = immunomodulatory therapy) the presence of autoimmunity in people suffering from psychiatric disorders (psychosis).

    Led by Frederic Villega (CHU Bordeaux/IINS) and involving 9 University Hospitals across France, the project involves psychiatrists, child psychiatrists, neuropaediatricians and researchers. Psychiatrists Marion Leboyer from the Fondamental Foundation, Bruno Aouizerate, David Misdrahi, Sebastien Gard and Anouck Amestoy from Bordeaux Charles Perrens CHU, will be working hand in hand with researchers from Laurent Groc's IINS team (Delphine Bouchet, Olivier Nicole, Julien Dupuis, Helene Grea) and the Bordeaux CHU immunology department team (Isabelle Pellegrin, Patrick Blanco, Cecile Bordes).

    The project was born in 2019 thanks to collaborative work between the research team of Laurent Groc (CNRS/University of Bordeaux), and the neuropaediatrician Frederic Villega, with the support of the Clinical Research Department of Bordeaux University Hospital.

    In terms of funding, the project was supported by the the French government with the “Direction Generale de l'Offre de Soins”. The strength of this project lies both in the clinical question and in the fundamental and technological advances made by the IINS research laboratory. IINS researchers have built a diagnostic platform, coordinated by Delphine Bouchet (CNRS Research Engineer). It enables the presence of pathological autoantibodies to be detected with a high degree of reliability, which is a fundamental issue in this field. This effort began more than 10 years ago with the support of the “Fondation de le Recherche Medicale” (FRM), the Fondation “FondaMental”, and more recently, thanks to the award in 2019 of the SPARK prize from the University of Bordeaux. Thanks to the emergence of this innovative platform, the clinical project can now be rolled out with a budget of one million euros.

    The project has also had a long road ahead, with submissions to many institutions (“Agence nationale de securité du medicament", ethics committees, etc.) and the covid pandemic. Nevertheless, diagnosis and treatment of the disease will be able to begin in October 2023.

    The prospects for the PHRC TiM-DepisT project are therefore significant. Between 2024 and 2027, researchers plan to carry out diagnostic research on 1,000 patients. The aim is to detect and provide access to immunotherapy treatment for several dozens of them. This unprecedented system opens up a host of possibilities for the benefit of medicine, which is in the midst of a revolution as a result of the discovery of the multiple implications of autoimmunity.

    Frederic Villega has a few words to say about the PHRC TiM-DepisT project :

    "As a clinician at the CHU, who has been working with Laurent Groc and his team for many years, I have structured this bridge between the clinical and the technological. This enables us to transfer elements of major fundamental discoveries for the benefit of healthcare! In this way, I've been able to bring together the strengths of Bordeaux University Hospital and the IINS to build an incredibly ambitious project that will provide answers to major burning questions about the new concept of immuno-psychiatry. [...] Laurent Groc was the researcher who, with his team and his international partners, climbed the first steps of an immense edifice concerning the physiopathology of psychiatric illnesses. This project represents immense hope for all mankind. It is, of course, one of many examples of the importance of research to healthcare and the quality of life of the men and women of tomorrow. [...] The aim of this research project is to answer 2 major questions in the context of mental health care: How prevalent is dysimmunity among the many factors involved in the pathophysiology of the diagnosis of psychosis? And to what extent can these patients, with an autoimmunity, respond to immunomodulatory therapy? This project could prove to be a major global turning point in psychiatric diagnosis and treatment, offering millions of families the hope of a brighter future!

    NMDA receptor autoantibodies primarily impair the extrasynaptic compartment, BRAIN - May 24

    Zoe Jamet, Camille Mergaux, Morgane Meras, Delphine Bouchet, Frédéric Villega, Jakob Kreye, Harald Prüss, Laurent Groc

    Brain. 2024-05-17

    DOI : https://doi.org/10.1093/brain/awae163                                                                                    

    Summary

    Autoantibodies directed against the N-methyl-D-aspartate receptor (NMDAR-Ab) are pathogenic immunoglobulins detected in patients suffering from NMDAR encephalitis. NMDAR-Ab alter the receptor membrane trafficking, synaptic transmission and neuronal network properties, leading to patients’ neurological and psychiatric symptoms. Patients often have very little neuronal damage but rapid and massive (treatment-responsive) brain dysfunctions related to unknown early mechanism of NMDAR-Ab. Our understanding of this early molecular cascade remains surprisingly fragmented.

    Here, we used a combination of single molecule-based imaging of membrane proteins to unveil the spatio-temporal action of NMDAR-Ab onto live hippocampal neurons.

    We first demonstrate that different clones of NMDAR-Ab primarily affect extrasynaptic -and not synaptic- NMDAR. In the first minutes, NMDAR-Ab increase extrasynaptic NMDAR membrane dynamics, de-clustering its surface interactome. NMDAR-Ab also rapidly reshuffle all membrane proteins located at the extrasynaptic compartment. Consistent with this alteration of multiple proteins, NMDAR-Ab effects were not mediated through the sole interaction between NMDAR and EphB2 receptor. At the long-term, NMDAR-Ab reduce NMDAR synaptic pool by slowing down receptor membrane dynamics in a cross-linking independent manner. Remarkably, exposing only extrasynaptic NMDAR to NMDAR-Ab was sufficient to produce their full-blown effect on synaptic receptors.

    Collectively, we demonstrate that NMDAR-Ab first impair extrasynaptic proteins, and then the synaptic ones. These data shed thus new, and unsuspected, lights on the mode of action of NMDAR-Ab and likely to our understanding of (extra)synaptopathies.

    Selected Publications

  • Grassi D, Idziak A, Lee A, Calaresu I, Sibarita JB, Cognet L, Nägerl UV, Groc L.
  • Nanoscale and functional heterogeneity of the hippocampal extracellular space. Cell Rep (2023)
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  • González-González IM, Gray JA, Ferreira J, Conde-Dusman MJ, Bouchet D, Perez-Otaño I, Groc L.
  • GluN3A subunit tunes NMDA receptor synaptic trafficking and content during postnatal brain development. Cell Rep. (2023)
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  • Dupuis JP, Nicole O, Groc L.
  • NMDA receptor functions in health and disease: Old actor, new dimensions. Neuron (2023)
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  • Paviolo C, Ferreira JS, Lee A, Hunter D, Calaresu I, Nandi S, Groc L, Cognet L
  • Near-Infrared Carbon Nanotube Tracking Reveals the Nanoscale Extracellular Space around Synapses. Nano Lett. (2022)
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  • Mar Petit-Pedrol, Laurent Groc
  • Regulation of membrane NMDA receptors by dynamics and protein interactions J. Cell Biol. (2021)
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  • Etchepare L, Gréa H, Durand P, Bouchet D, Groc L
  • NMDA receptor membrane dynamics tunes the firing pattern of midbrain dopaminergic neurons J. Physiol (2021)
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  • Hosokawa T, Liu PW, Cai Q, Ferreira JS, Levet F, Butler C, Sibarita JB, Choquet D, Groc L, Hosy E, Zhang M, Hayashi Y
  • CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation Nature Neurosci. (2021)
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  • Wollmuth LP, Chan K, Groc L
  • The diverse and complex modes of action of anti-NMDA receptor autoantibodies Neuropharmacol. (2021)
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  • Espana A, Seth H, Jézéquel J, Huang T, Bouchet D, Lepleux M, Gréa H, Bechter K, Schneider M, Hanse E, Groc L
  • Alteration of NMDA receptor trafficking as a cellular hallmark of psychosis Translational Psychiatry (2021)
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  • Ferreira JS, Dupuis JP, Kellermayer B, Bénac N, Manso C, Bouchet D, Levet F, Butler C, Sibarita JB, Groc L.
  • Distance-dependent regulation of NMDAR nanoscale organization along hippocampal neuron dendrites PNAS (2020)
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  • Johansson EM, Bouchet D, Tamouza R, Ellul P, Morr AS, Avignone E, Germi R, Leboyer M, Perron H, Groc L
  • Human endogenous retroviral protein triggers deficit in glutamate synapse maturation and behaviors associated with psychosis Science Adv. (2020)
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  • Groc L, Choquet D
  • Linking glutamate receptor movements and synapse function Science (2020)
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  • Ciappelloni S, Bouchet D, Dubourdieu N, Boué-Grabot E, Kellermayer B, Manso C, Marignier R, Oliet SHR, Tourdias T, Groc L
  • Aquaporin-4 Surface Trafficking Regulates Astrocytic Process Motility and Synaptic Activity in Health and Autoimmune Disease Cell Reports (2019)
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  • Kellermayer B, Ferreira JS, Dupuis J, Levet F, Grillo-Bosch D, Bard L, Linarès-Loyez J, Bouchet D, Choquet D, Rusakov DA, Bon P, Sibarita JB, Cognet L, Sainlos M, Carvalho AL, Groc L
  • Differential Nanoscale Topography and Functional Role of GluN2-NMDA Receptor Subtypes at Glutamatergic Synapses Neuron (2018)
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  • Jézéquel J, Johansson EM, Leboyer M, Groc L
  • Pathogenicity of Antibodies against NMDA Receptor: Molecular Insights into Autoimmune Psychosis Trends Neurosci. (2018)
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  • Jézéquel J, Johansson EM, Dupuis JP, Rogemond V, Gréa H, Kellermayer B, Hamdani N, Le Guen E, Rabu C, Lepleux M, Spatola M, Mathias E, Bouchet D, Ramsey AJ, Yolken RH, Tamouza R, Dalmau J, Honnorat J, Leboyer M, Groc L
  • Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients Nature Commun. (2017)
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  • Ferreira JS, Papouin T, Ladépêche L, Yao A, Langlais VC, Bouchet D, Dulong J, Mothet JP, Sacchi S, Pollegioni L, Paoletti P, Oliet SHR, Groc L
  • Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses eLife (2017)
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  • Godin AG, Varela JA, Gao Z, Danné N, Dupuis JP, Lounis B, Groc L*, Cognet L*
  • Single-nanotube tracking reveals the nanoscale organization of the extracellular space in the live brain Nature Nanotechnol. (2017)
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  • Varela JA, Dupuis JP, Etchepare L, Espana A, Cognet L, Groc L
  • Targeting neurotransmitter receptors with nanoparticles in vivo allows single-molecule tracking in acute brain slices Nature Commun. (2016)
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  • Murphy-Royal C, Dupuis JP, Varela JA, Panatier A, Pinson B, Baufreton J, Groc L*, Oliet SH*
  • Surface diffusion of astrocytic glutamate transporters shapes synaptic transmission Nature Neurosci. (2015)
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  • Ladepeche L, Dupuis JP, Bouchet D, Doudnikoff E, Yang L, Campagne Y, Bézard E, Hosy E, Groc L
  • Surface dynamics of GluN2B-NMDA receptors controls plasticity of maturing glutamate synapses EMBO J. (2014)
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  • Ladepeche L, Dupuis JP, Bouchet D, Doudnikoff E, Yang L, Campagne Y, Bézard E, Hosy E, Groc L
  • Single-molecule imaging of the functional crosstalk between surface NMDA and dopamine D1 receptors PNAS (2013)
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  • Zhang H, Etherington LA, Hafner AS, Belelli D, Coussen F, Delagrange P, Chaouloff F, Spedding M, Lambert JJ, Choquet D, Groc L
  • Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule Molecular Psychiatry (2013)
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  • Mikasova L, De Rossi P, Bouchet D, Georges F, Rogemond V, Didelot A, Meissirel C, Honnorat J, Groc L
  • Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis Brain (2012)
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  • Bard L, Sainlos M, Bouchet D, Cousins S, Mikasova L, Breillat C, Stephenson FA, Imperiali B, Choquet D, Groc L
  • Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins PNAS (2010)
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  • Krugers HJ, Hoogenraad CC, Groc L
  • The stress hormone corticosterone conditions AMPAR surface trafficking and synaptic potentiation Nature Review Neurosci. (2010)
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  • Groc L, Choquet D, Chaouloff F
  • The stress hormone corticosterone conditions AMPAR surface trafficking and synaptic potentiation Nature Neurosci. (2008)
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  • Groc L, Heine M, Cousins SL, Stephenson FA, Lounis B, Cognet L, Choquet D
  • NMDA receptor surface mobility depends on NR2A-2B subunits PNAS (2006)
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  • Groc L, Gustafsson B, Hanse E
  • AMPA signalling in nascent glutamatergic synapses: there and not there! Trends Neurosci. (2006)
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  • Groc L, Heine M, Cognet L, Brickley K, Stephenson FA, Lounis B, Choquet D
  • Differential activity-dependent regulation of the lateral mobilities of AMPA and NMDA receptors Nature Neurosci. (2004)
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    Members

    « Researcher »

    DUPUIS Julien Researcher julien.dupuis@u-bordeaux.fr +33533514762
    GREA Helene Researcher helene.grea@u-bordeaux.fr +33533514762
    GROC Laurent Researcher laurent.groc@u-bordeaux.fr +33533514702
    NICOLE Olivier Researcher olivier.nicole@u-bordeaux.fr +33533514781
    Villega Frédéric Researcher frederic.villega@u-bordeaux.fr +33533514762

    « Technical Staff »

    BOUCHET TESSIER Delphine Technical staff delphine.bouchet@u-bordeaux.fr +33533514762
    BOULARAND Romain Technical staff romain.boularand@u-bordeaux.fr +33533514700
    BUCKENMEYER Adèle Technical staff adele.buckenmeyer@u-bordeaux.fr +33533514700
    GRARD Thomas Technical staff thomas.grard@u-bordeaux.fr +33533514700
    LECHANOINE Thomas Technical staff thomas.lechanoine@u-bordeaux.fr +33533514700
    MERAS Morgane Technical staff morgane.meras@u-bordeaux.fr +33533514781

    « Postdoc »

    CALARESU Ivo Postdoc ivo.calaresu@u-bordeaux.fr +33533514700
    FERNANDES Dominique Postdoc dominique.fernandes@u-bordeaux.fr +33533514700

    « PhD student »

    BENAC Nathan PhD student nathan.benac@u-bordeaux.fr +33533514781
    MERGAUX Camille PhD student camille.mergaux@u-bordeaux.fr +33533514700
    SIMOES Flavia PhD student flavia.simoes@u-bordeaux.fr +33533514700
    UYTTERSPROT Floriane PhD student floriane.uyttersprot@u-bordeaux.fr +33533514700
    VILLETELLE Léa PhD student lea.villetelle@u-bordeaux.fr +33533514781

    « Alumni & Guests »

    ALUMNI and GUESTS

    Former group members

    • Lucie BARD (2006-2010) PhD student
    • Hongyu ZHANG (2009-2011) Post-doc
    • Lenka MIKASOVA (2009-2012) Post-doc
    • François GEORGES (2011-2013) CNRS researcher
    • Christelle GLANGETAS (2011-2013) PhD student
    • Delphine GIRARD (2011-2013) CNRS engineer
    • Laurent LADEPECHE (2009-2013) PhD student
    • Ciaran MURPHY-ROYAL (2010-2014) PhD student
    • Agnès ESPANA (2011-2014) Post-doc
    • Aurelia LE DANTEC (2012-2014) CNRS engineer
    • Juan VARELA (2011-2015) Post-doc
    • Charlotte BERTOT (2013-2016) PhD student
    • Julie JEZEQUEL (2011-2017) PhD student
    • Pauline DURAND (2014-2017) CNRS engineer
    • Laetitia ETCHEPARE (2012-2017) PhD student
    • Blanka KELLERMAYER (2014-2017) PhD student
    • Silvia CIAPPELLONI (2013-2017) Post-doc
    • Sébastien HABE (2016-2017) CNRS engineer
    • Marilyn LEPLEUX (2015-2018) CNRS engineer
    • Audrey BARRANGER (2017-2019) CNRS engineer
    • Ezequiel SARACENO (2017-2019) Post-doc
    • Tingting HUANG (2017-2019) PhD student
    • Pauline LETARD (2015-2019) PhD student
    • Elise GOYET (2017-2019) CNRS engineer
    • Emily JOHANSSON (2013-2020) Post-doc
    • Elena AVIGNONE (2013-2020) Bordeaux University researcher
    • Alexandra FERNANDES (2015-2020) PhD student
    • François MAINGRET (2013-2021) CNRS researcher
    • Joana FERREIRA (2013-2021) Post-Doc
    • Diego GRASSI (2018-2021) Post-Doc
    • Elodie COUGOUILLES (2020) UB engineer
    • Constance MANSO (2018-2021) CNRS/UB engineer
    • Mar PETIT-PEDROL (2020-2022) Post-Doc
    • Laurine BASTARDO (2020-2023) CNRS engineer
    • Theo BAURBERG (2020-2023) CNRS engineer
    • Daniel HUNTER (2019-2023) PhD Student

    Guests

    • Inma GONZALEZ (2011-2012) Pamplona University
    • Amber KERKHOFS (2012) Utrecht University
    • Yuki MIURA (2013-2014) Tsukuka University
    • Pr. Marion LEBOYER (2016) Hopital Mondor, Fondation FondaMental
    • Kevin JEHASSE (2019) Liège University
    • Nila VAN OVERBEEK (2019-2020) Amsterdam University
    • Pin Wu LIU (2020) Kyoto University Graduate School of Medicine
    • Alessandro CHIOINO (2022) Lausanne University
    • Vanesa SALAZAR SANCHEZ (2022), Edimbourg University
    • Catarina RODRIGUES (2022-2023) ERASMUS - Coimbra University
    • Estibaliz MAUDES (2023) Barcelona University
    • Andres BARRIA (2023) Professor of Physiology & Biophysics, University of Washington