Developmental Brain Physiology and Pathology

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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

Glutamate - Dopamine receptor interplay: from physiology to brain disorders

Psychotomimetic drugs: molecular, cellular and behavioural mechanisms of action

Immunoglobulin dynamics in the brain

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

Immun'Optic Screening Platform

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)
MORE

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)
MORE

Dupuis JP, Nicole O, Groc L.

NMDA receptor functions in health and disease: Old actor, new dimensions. Neuron (2023)
MORE

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)
MORE

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 »

BOISEL Eva	Technical staff	eva.boisel@u-bordeaux.fr	+33533514700
BOUCHET TESSIER Delphine	Technical staff	delphine.bouchet@u-bordeaux.fr	+33533514762
BOULARAND Romain	Technical staff	romain.boularand@u-bordeaux.fr	+33533514700
GAIKWAD Pranay	Technical staff	pranay.gaikwad@u-bordeaux.fr	+33533514700
GIRARD Jordan	Technical staff	jordan.girard@u-bordeaux.fr	+33533514748
GRARD Thomas	Technical staff	thomas.grard@u-bordeaux.fr	+33533514700
JEGO Madelyne	Technical staff	madelyne.jego@u-bordeaux.fr	+33533514700
LOPES FERREIRA Constança	Technical staff	constanca.lopes-ferreira@u-bordeaux.fr	+33533514700
MERAS Morgane	Technical staff	morgane.meras@u-bordeaux.fr	+33533514781
SEBGHATI MAMAGHANI Zahra	Technical staff	zahra.sebghati-mamaghani@etu.u-bordeaux.fr	+33533514700

« Postdoc »

CALARESU Ivo	Postdoc	ivo.calaresu@u-bordeaux.fr	+33533514700
DEMBITSKAYA Yulia	Postdoc	iuliia.dembitskaia@u-bordeaux.fr	+33533514700
FERNANDES Dominique	Postdoc	dominique.fernandes@u-bordeaux.fr	+33533514700
OKUDA Kosuke	Postdoc	kosuke.okuda@u-bordeaux.fr	+33533514700
SAMMARI Malika	Postdoc	malika.sammari@u-bordeaux.fr	+33533514700

« PhD student »

MERGAUX Camille	PhD student	camille.mergaux@u-bordeaux.fr	+33533514700
SIMOES Flavia	PhD student	flavia.simoes@u-bordeaux.fr	+33533514700
VILLETELLE Léa	PhD student	lea.villetelle@u-bordeaux.fr	+33533514781

« Student »

AMOUZGAR Mana	Student	mana.amouzgar@etu.u-bordeaux.fr	+33533514700
IVASCHUK Sophia	Student	sophia.ivaschuk@etu.u-bordeaux.fr	+33533514700
RIBOULET Chloé	Student	chloe.riboulet@u-bordeaux.fr	+33533514700

« 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