Research Projects

Team Project Summary

MORE

Cytoskeleton and membrane interplay in synaptic organization and transmission (Anna Brachet).

MORE

Chemical Biology and Protein Engineering (Matthieu Sainlos)

MORE

Impact of auxiliary proteins on AMPAR transport, trafficking and physiology (Françoise Coussen).

MORE

nanoscale excitatory synaptic physiology (Eric Hosy).

MORE

Contribution of AMPAR surface trafficking to Short and long term synaptic plasticity (Daniel Choquet)

MORE

Synapse dysfunction in neurodevelopmental disorders (Eric Hosy, Daniel Choquet)

MORE

Partnerships

MORE

Expertise

Super Resolution Microscopy

Slice physiology

Chemical biology, Protein Engineering

Biochemistry

News

Co-organization and coactivation of AMPAR, NMDAR, and mGluR

Nanoscale co-organization and coactivation of AMPAR, NMDAR, and mGluR at excitatory synapses.

The nanoscale co-organization of neurotransmitter receptors facing presynaptic release sites is a fundamental determinant of their coactivation and of synaptic physiology. At excitatory synapses, how endogenous AMPARs, NMDARs, and mGluRs are co-organized inside the synapse and their respective activation during glutamate release are still unclear. Combining single-molecule super resolution microscopy, electrophysiology, and modeling, we determined the average quantity of each glutamate receptor type, their nanoscale organization, and their respective activation. We observed that NMDARs form a unique cluster mainly at the center of the PSD, while AMPARs segregate in clusters surrounding the NMDARs.mGluR5 presents a different organization and is homogenously dispersed at the synaptic surface. From these results, we build a model predicting the synaptic transmission properties of a unitary synapse, allowing better understanding of synaptic physiology.

Authors: Julia Goncalves, Tomas M. Bartol, Côme Camus, Florian Levet, Ana Paula Menegolla,Terrence J. Sejnowski, Jean-Baptiste Sibarita, Michel Vivaudou, Daniel Choquet and Eric Hosy

- Publication in PNAS, June 8, 2020 https://doi.org/10.1073/pnas.1922563117
- Contact: Eric Hosy

AMPA receptor nanoscale dynamic organization and synaptic plasticities

Review on “AMPA receptor nanoscale dynamic organization and synaptic plasticities” in Current Opinion in Neurobiology 2020

The emergence of new imaging techniques and molecular tools has refreshed our understanding of the principles of synaptic transmission and plasticity. Superresolution imaging and biosensors for measuring enzymatic activities in live neurons or neurotransmitter levels in the synaptic cleft are giving us an unprecedented integrated and nanoscale view on synaptic function. Excitatory synapses are now conceptualized as organized in subdomains, enriched with specific scaffolding proteins and glutamate receptors, molecularly organized with respect to the pre-synaptic source of glutamate.

This new vision of basic synaptic transmission changes our understanding of the molecular modifications which sustain synaptic plasticities. Long-term potentiation can no longer be explained simply by an increase in receptor content at the synapse. We review here the latest data on the role of nanoscale and dynamic organization of AMPA type glutamate receptors on synaptic transmission at both basal state and during short and long-term plasticities.

 Current Opinion in Neurobiology - Volume 63, August 2020, Pages 137-145 https://doi.org/10.1016/j.conb.2020.04.003
 Contacts: Daniel Choquet and Eric Hosy

A discrete presynaptic vesicle cycle for neuromodulator receptors - Neuron, December 2019

A major function of GPCRs is to inhibit presynaptic neurotransmitter release, requiring ligand-activated receptors to couple locally to effectors at terminals. The current understanding of how this is achieved is through receptor immobilization on the terminal surface. Here, we show that opioid peptide receptors, GPCRs that mediate highly sensitive presynaptic inhibition, are instead dynamic in axons. Opioid receptors diffuse rapidly throughout the axon surface and internalize after ligand-induced activation specifically at presynaptic terminals. We delineate a parallel regulated endocytic cycle for GPCRs operating at the presynapse, separately from the synaptic vesicle cycle, which clears activated receptors from the surface of terminals and locally reinserts them to maintain the diffusible surface pool. We propose an alternate strategy for achieving local control of presynaptic effectors that, opposite to using receptor immobilization and enforced proximity, is based on lateral mobility of receptors and leverages the inherent allostery of GPCR-effector coupling.

Damien Jullié, Miriam Stoeber, Jean-Baptiste Sibarita, Hanna L. Zieger, Thomas M. Bartol, Seksiri Arttamangkul, Terrence J. Sejnowski, Eric Hosy, and Mark von Zastrow

- Neuron. 2019 Dec 5 - doi: 10.1016/j.neuron.2019.11.016.
- Contact: Eric Hosy

Multicolor Spectrin labeling (ML Jobin)

This is a rat hippocampal neuron in culture stained with a series of markers

Nature Neuroscience Review - Choquet D., Sainlos M. and Sibarita J.B.

We review the latest developments for labelling and functionalizing proteins with small localization and functionalized reporters. We present how these molecular tools are combined with the development of a wide variety of imaging methods that break either the diffraction barrier or the tissue penetration depth limits. We put these developments in perspective to emphasize how they will enable step changes in our understanding of the brain.

MORE

BRAIN_2030 «Grand Programme de Recherche» de l'université de Bordeaux

The BRAIN_2030 project (“Bordeaux Region Aquitaine Initiative for the future of Neurosciences”), submitted by Bordeaux Neurocampus within the “GPR - Major Research Program” of the University of Bordeaux, and headed by Daniel Choquet, has just been approved. It is one of the 7 projects selected out of the 15 submitted in June 2020.

A dialogue phase is planned to validate the final budget that will be allocated for the period 2021-2025. Additional funding for an additional period will be granted after an interim evaluation in 2025.

The project starts in September 2021.

+ Find more details on the Université of Bordeaux (UB) and the Bordeaux Neurocampus (BN) websites.

Access the hidden side of neuronal proteins through the expansion of the genetic code

Progress in biological imaging is intrinsically linked to advances in labeling methods. The explosion in the development of high-resolution and super-resolution imaging calls for new approaches to label targets with small probes. These should allow to faithfully report the localization of the target within the imaging resolution – typically nowadays a few nanometers - and allow access to any epitope of the target, in the native cellular and tissue environment. We report here the development of a complete labeling and imaging pipeline using genetic code expansion and non-canonical amino acids in neurons that allows to fluorescently label masked epitopes in target transmembrane proteins in live neurons, both in dissociated culture and organotypic brain slices. This allows us to image the differential localization of two AMPA receptor (AMPAR) auxiliary subunits of the transmembrane AMPAR regulatory protein family in complex with their partner with a variety of methods including widefield, confocal, and dSTORM super-resolution microscopy.

Authors: Diogo Bessa-Neto & Gerti Beliu, Alexander Kuhlemann, Valeria Pecoraro, Sören Doose, Natacha Retailleau, Nicolas Chevrier, David Perrais, Markus Sauer & Daniel Choquet

Bioorthogonal labeling of transmembrane proteins with non-canonical amino acids unveils masked epitopes in live neurons.
Nature Communications (November 2021) DOI: 10.1038/s41467-021-27025-w

Contact: Daniel Choquet

+ Cf. INSB website (French) here
+ Cf. the press release on the University of Würzburg website here

Daniel Choquet: prix 2022 de l’Academie nationale des sciences, belles lettres et arts de Bordeaux

Academie nationale des sciences, belles lettres et arts de Bordeaux aims to help develop the ideas, work and research of Academicians. Each year, it rewards in particular personalities for their work or their research or for all of their work in the field of science, literature or the arts.

Thus, in 2022, it was Daniel Choquet, CNRS research director, who was awarded "le grand prix 2022 de l’Academie nationale des sciences, belles lettres et arts de Bordeaux"! Indeed, he achieved this distinction thanks to his main scientific achievement: the discovery that neurotransmitter receptors are in constant motion in the neuronal membrane and that the regulation of this traffic profoundly regulates synaptic transmission. Daniel Choquet will receive his award on March 28 from Pierre Hurmic, Mayor of Bordeaux.

Learn more about: Le grand prix 2022 de l’Academie nationale des sciences, belles lettres et arts de Bordeaux

They talk about it too (articles in French): INSB and Bordeaux Neurocampus

Do you want to know more? Nolwenn Cloarec, communication officer: nolwenn.cloarec@u-bordeaux.fr

Regulation of different phases of AMPA receptor intracellular transport by 4.1N and SAP97, eLife

Caroline Bonnet1, Justine Charpentier1, Natacha Retailleau1, Daniel Choquet1,2, Françoise Coussen1*
1University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, Bordeaux, France; 2Bordeaux Imaging Center, Bordeaux, France

eLife. 2023-04-20

DOI: https://doi.org/10.7554/eLife.85609

Françoise Coussen, Director of research at the CNRS at IINS worked on AMPAR intracellular transport and directed this work helped by Daniel Choquet. Caroline Bonnet, PhD student, performed the experiments helped by Justine Charpentier who performed all biochemistry experiments and by Natacha Retailleau (molecular biology).

Find the explanations of the scientists of this publication

Identification of the molecular mechanisms regulating the intracellular transport of glutamate receptors: a new pathway for controlling synaptic plasticity

"The modulation of the efficiency of synaptic transmission between neurons is one of the fundamental processes of memory and learning phenomena. This regulation of the strength of synaptic transmission is largely driven by changes in the number of receptors present at the synapse. In this work, the researchers identify a new mechanism for controlling the establishment of receptors at the level of the synapse through the control of their intracellular transport.

Neurotransmitter receptors, and in particular glutamate receptors, are concentrated in synapses in front of neurotransmitter release sites. However, in the process of their biogenesis, these receptors are synthesized at the level of the endoplasmic reticulum, most of the time several hundred microns from the synapses. They must therefore be transported to the synapses. Our previous work had made possible to visualize for the first time the intracellular transport of AMPA-type glutamate receptors, responsible for the majority of the rapid excitatory transmission between neurons. These receptors are transported rapidly (1-2 microns per second) in vesicles circulating on the microtubules using molecular motors. We observed that, surprisingly, this transport was strongly regulated by neuronal activity.

In this new work, we have identified the molecular mechanisms responsible for these regulations. The cytosolic C-terminal domain of the AMPAR GluA1 subunit is specifically associated with two proteins, 4.1 N and SAP97. We analyzed how interactions between GluA1 and 4.1N or SAP97 regulate GluA1 transport and its exocytosis under basal conditions and after induction of synaptic plasticity (LTP). Our results identify differential roles of 4.1N and SAP97 in controlling the different phases of transport and membrane integration of GluA1.

This work opens new perspectives in understanding the molecular mechanisms that control the establishment and maintenance of glutamate receptors at the synapse during synaptic plasticity."

EURAS Project: Development of New Effective Therapies for RASopathies

The EURAS project is a response to the "Horizon 2020 Projects" Call for Proposals, focusing on the development of new effective therapies for rare diseases. With a budget of 80 million euros, this call provides funding of 9 million euros for the EURAS project over a duration of 4 years.

Coordinated at the level of Bordeaux by Eric Hosy, a researcher at CNRS and member of the "Dynamics of Organization and Synaptic Functions" (team Choquet), and promoted by the Interdisciplinary Institute of Neuroscience, the project stems from the initiative of patient associations carrying mutations in genes regulating the RAS protein (SynGAP Elternhilfe), with SynGAP1 being the most well-known. Thus, the EURAS project brings together 16 European teams from 13 countries, covering all domains of neuroscience, from genetics to molecule screening, including electrophysiology, behavior, and stem cell studies.

The main objectives of the project are as follows: (i) establishing a database of physiological data and human samples accessible to the entire scientific community, encompassing a large number of patients across Europe, (ii) understanding how these neurodevelopmental diseases affect the establishment of the neural network, and (iii) screening drug libraries to determine if certain drugs improve neuronal physiology.

The project is based on the fact that there are over 15,000 drugs already on the market, but it is highly unlikely that all of these drugs have been tested on the few hundred to thousand patients with these rare diseases worldwide. However, some of these drugs likely target the RAS regulatory pathway, either directly or indirectly. Therefore, the researchers involved in this project will carry out in vitro tests on all these molecules. The aim is to identify those that improve the development of neurons in patients (derived from stem cells).

The contribution of the Bordeaux laboratory is to identify common molecular signatures among different RASopathies and test various drugs to restore/ improve neuronal development. This work will be carried out in collaboration with the Bordeaux Imaging Center, a major imaging center in Bordeaux.

This funding adds to the research dynamics in Bordeaux, where fundamental research converges with clinical practice. This dynamic had already been initiated by a clinical research project led by geneticists Cyril Goizet and Chloé Angelini, which enabled the collection of human data for Bordeaux projects, including those of Eric Hosy on neurodevelopmental disorders such as intellectual disability and autism.

Ultimately, the expected potential benefits for patients are significant, as it will not only improve our understanding of neurogenetic diseases but also directly enhance the quality of life for patients and their caregivers. If a drug already on the market passes the tests, the lengthy process of safety validation will not be necessary, allowing it to be quickly administered to assess its actual effectiveness in patients.

Selected Publications

Angela M Getz, Mathieu Ducros, Christelle Breillat, Aurélie Lampin-Saint-Amaux, Sophie Daburon, Urielle François, Agata Nowacka, Mónica Fernández-Monreal, Eric Hosy, Frédéric Lanore, Hanna L Zieger, Matthieu Sainlos, Yann Humeau, Daniel Choquet

High-resolution imaging and manipulation of endogenous AMPA receptor surface mobility during synaptic plasticity and learning Science Advances (2022)
Display the article MORE

Choquet D., Sainlos M. and Sibarita J.B.

Advanced imaging and labelling methods to decipher brain cell organization and function Nature reviews Neuroscience (2021)
Display the article MORE

Tomohisa Hosokawa, Pin-Wu Liu, Qixu Cai, Joana S. Ferreira, Florian Levet, Corey Butler, Jean-Baptiste Sibarita, Daniel Choquet, Laurent Groc, Eric Hosy, Mingjie Zhang and Yasunori Hayashi 

CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation Nature Neuroscience (2021)
Display the article MORE

Diogo Bessa-Neto, Gerti Beliu, Alexander Kuhlemann, Valeria Pecoraro, Sören Doose, Natacha Retailleau, Nicolas Chevrier, David Perrais, Markus Sauer & Daniel Choquet

Bioorthogonal labeling of transmembrane proteins with non-canonical amino acids unveils masked epitopes in live neurons Nature Communications (2021)
Display the article MORE

Laurent Groc & Daniel Choquet

Linking glutamate receptor movements and synapse function Science (2020)
Display the article MORE

Julia Goncalves, Tomas M Bartol, Côme Camus, Florian Levet, Ana Paula Menegolla, Terrence J Sejnowski, Jean-Baptiste Sibarita, Michel Vivaudou, Daniel Choquet, Eric Hosy

Nanoscale co-organization and coactivation of AMPAR, NMDAR, and mGluR at excitatory synapses Proc Natl Acad Sci U S A (2020)
MORE

Tiago Campelo, Elisabete Augusto, Nicolas Chenouard, Aron de Miranda, Vladimir Kouskoff, Come Camus, Daniel Choquet, Frédéric Gambino

AMPAR-Dependent Synaptic Plasticity Initiates Cortical Remapping and Adaptive Behaviors during Sensory Experience Cell Report (2020)
Display the article MORE

Florelle Domart, Peter Cloetens, Stéphane Roudeau, Asuncion Carmona, Emeline Verdier, Daniel Choquet, Richard Ortega

Correlating STED and synchrotron XRF nano-imaging unveils cosegregation of metals and cytoskeleton proteins in dendrites eLife (2020)
Display the article MORE

Humeau, Y. and Choquet, D.

The next generation of approaches to investigate the link between synaptic plasticity and learning. Nature Neuroscience (2019)
Display the article MORE

Charlotte Rimbault, Kashyap Maruthi, Christelle Breillat, Camille Genuer, Sara Crespillo, Virginia Puente-Muñoz, Ingrid Chamma, Isabel Gauthereau, Ségolène Antoine, Coraline Thibaut, Fabienne Wong Jun Tai, Benjamin Dartigues, Dolors Grillo-Bosch, Stéphane Claverol, Christel Poujol, Daniel Choquet, Cameron D Mackereth, Matthieu Sainlos

Engineering selective competitors for the discrimination of highly conserved protein-protein interaction modules Nature Communication (2019)
Display the article MORE

Emilie Hangen, Fabrice P Cordelières, Jennifer D Petersen, Daniel Choquet, Françoise Coussen

Neuronal Activity and Intracellular Calcium Levels Regulate Intracellular Transport of Newly Synthesized AMPAR Cell Report (2018)
Display the article MORE

Penn, A.C., Zhang, C.L., Georges, F., Royer, L., Breillat, C., Hosy, E., Petersen, J.D., Humeau, Y., and Choquet, D.

Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors Nature (2017)
Display the article MORE

Audrey Constals, Andrew C Penn, Benjamin Compans, Estelle Toulmé, Amandine Phillipat, Sébastien Marais, Natacha Retailleau, Anne-Sophie Hafner, Françoise Coussen, Eric Hosy, Daniel Choquet

Glutamate-induced AMPA receptor desensitization increases their mobility and modulates short-term plasticity through unbinding from Stargazin Neuron (2015)
Display the article MORE

Anne-Sophie Hafner, Andrew C Penn, Dolors Grillo-Bosch, Natacha Retailleau, Christel Poujol, Amandine Philippat, Françoise Coussen, Matthieu Sainlos, Patricio Opazo, Daniel Choquet

Lengthening of the Stargazin Cytoplasmic Tail Increases Synaptic Transmission by Promoting Interaction to Deeper Domains of PSD-95 Neuron (2015)
Display the article MORE

Deepak Nair, Eric Hosy, Jennifer D Petersen, Audrey Constals, Gregory Giannone, Daniel Choquet, Jean-Baptiste Sibarita

Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95 Journal of Neuroscience (2013)
Display the article MORE

Heine, M., Groc, L., Frischknecht, R., Beique, J.C., Lounis, B., Rumbaugh, G., Huganir, R.L., Cognet, L., and Choquet, D.

Surface mobility of postsynaptic AMPARs tunes synaptic transmission Science (2008)
Display the article MORE

Aren J Borgdorff and Daniel Choquet

Regulation of AMPA receptor lateral movements Nature (2002)
Display the article MORE

« Alumni & Guests »

Former group members, follow-up last known position

• Aren borgdorff - 1997-2000, Industry
• Arnauld Sergé - 1997-2001, Assistant professor Marseille
• Marianne Renner - 2004-2006, Professor, Paris
• Caroline Dequidt - 2004-2007, Industry
• Cécile Bats - 2004-2007, Post-doc, London
• Martin Heine - 2003-2007, Junior group leader, Magdeburg
• Enrica Petrini - 2005-2008, Post-doc, Genoa
• Cezar Tigaret - 2006-2009, Lecturer, Bristol
• Helge Ewers - 2007-2009, Group leader, Berlin
• Arnaud Frouin - 2007-2010, Labmanager, NYC
• Leandro Royer - 2009-2012, Post-doc, Boston
• Patricio Opazo - 2008-2013, Group leader, Brisbane
• Jary Delgado - 2009-2013, Post-doc, Chicago
• Deepak Nair - 2009-2013, Group leader, Bengalor
• Damien Jullié - 2009-2013, Post-doc, San Francisco
• Audrey Constal - 2010-2013, Teacher
• Axel Athane - 2011-2013, Industry
• Dolors Grillo, 2011-2013, Post-doc, Spain
• Anne-Sophie Hafner - 2010-2014, Post-doc, Frankfurt
• Isabelle Gautherau - 2012-2014, Industry
• Amandine Philippat - 2013-2015, Industry
• Andrew Penn - 2010-2015, Junior group leader, Sussex
• Hongyu Zhang - 2010-2015, Post-doc, University of Bergen
• Estelle Toulme - 2013-2015, Post-doc, Berlin
• Jennifer Petersen - 2009-2016, Post-doc, NIH
• Yulia Krapivkina - 2013-2016, Industry
• Ngoc Van Thi Nhu - 2013-2016, Engineer, Montpellier
• Emilie Hangen - 2014-2017
• Ségolène Antoine - 2015-2017, French Industry
• Sara Crespillo - 2015-2017, Post-doc, Cambridge
• Célia Michel - 2014-2017, French Industry
• Benjamin Compans - 2014-2018, Post-doc, London
• Lucile Pret - 2018, Engineer, London
• Julia Goncalves – 2015 – 2018, Engineer, Bordeaux Neurocampus
• Murielle Fevre - 2017-2018
• Camille Genuer - 2017-2018, Engineer, French Industry
• Carla Montecinos - 2013-2018, post-doc Bordeaux
• Charlotte Rimbault – 2014-2019, Post-doc, Copenhagen
• Magalie Martineau – 2015-2019, Post-doc, Paris
• Léa Claverie – 2015 - 2019, UK
• Florelle Domart - 2016-2019, Post-doc Goettingen
• David Perrais - 2011-2020, Group Leader
• Sylvia Sposini - 2018-2020, Post-doc, Bordeaux
• Lou Bouit - 2018-2020, Engineer, Bordeaux 
• Côme Camus - 2018-2021, Medical Intern, Bordeaux 
• Caroline Bonnet - 2017-2021
• Inès Gonzalès-Calvo - 2019-2021
• Valeria Pecoraro - 2019-2021

Guests

• Raffaella Adami, Pisa - January, June 2001
• Andres Villu Maricq, Utah - November 2003
• Radhika Reddy, Worley lab - June 2003
• Michael Ehlers, Duke University - March, September 2006
• Renatto Frischknecht, Gundelfinger lab - April 2006, September 2006
• Laura Andreae, Fine lab - April 2006, November 2006
• Anna Carbone, Plested Lab - January, April 2012
• Beulah Leitch, Otago University - October 2013
• Andrew Plested, FMP Berlin - October 2015, February 2016
• Nikolaj Riis Christensen, Copenhagen University - June-December 2017
• Anne Brunet, Stanford University - April-July 2019
• Pin Wu Liu, Kyoto University Graduate School of Medicine - January 2020
• Boram Lee, Johannes W. Hell UCDavis - January-June 2020

Jobs