2022-05-19 (MULLE Team) : Corlieve Therapeutics, co-funded by Christophe Mulle acquired by the biotech uniQure:
Corlieve Therapeutics co-funded by Christophe Mulle and Valérie Crépel (Inserm Marseille) acquired by the biotech uniQure. The acquisition of Corlieve Therapeutics by uniQure amounts to 250 million euros, of which the first initial settlement of 46.3 million euros finalizes the transaction.
The story of deeptech Corlieve Therapeutics is the meeting between leading researchers (Christophe Mulle and Valérie Crépel), an early investor and a high level entrepreneur. The union of two transfer offices has made it possible to promote and transfer technology that is beneficial for research and project leaders. 9 years, the time necessary for the research to lead to a successful transfer to a biotech company.
2022-04-22 (GROC Team) : Laurent Groc, laureate of the National Academy of Medicine 2021
Neurobiologist and CNRS Research Director at the Interdisciplinary Institute for Neuroscience, Laurent Groc has been awarded a prize by the French National Academy of Medicine for his work on the role of autoimmunity in the emergence of psychotic disorders.
Cf. CNRS website here
2022-04-04 (GROC Team) : Laurent Groc, Médaille d'argent du CNRS 2022
The CNRS Silver Medal is awarded to researchers for the originality, quality and importance of their work, recognized at national and international level.
Congratulations to Laurent Groc, CNRS research director and team leader at the IINS, one of the 22 laureates distinguished for this year 2022.
Cf. CNRS website here
2022-03-04 (SIBARITA Team) : Multi-dimensional spectral Single Molecule Localization Microscopy
Single molecule localization (SML) and tracking (SPT) techniques, such as (spt)PALM, (u/DNA)PAINT and quantum dot tracking, have given unprecedented insight into the nanoscale molecular organization and dynamics in living cells. They allow monitoring individual proteins with millisecond temporal resolution and high spatial resolution (<30 nm) by precisely localizing the point spread function (PSF) of individual emitters and tracking their position over time. While SPT methods have been extended to study the temporal dynamics and co-organization of multiple proteins, conventional experimental setups are restricted in the number of proteins they can probe simultaneously and usually have to tradeoff between the number of colors, the spatio-temporal resolution, and the field of view. Yet, localizing and tracking several proteins simultaneously at high spatial and temporal resolution within large field of views can provide important biological insights. By employing a dual-objective spectral imaging configuration compatible with live cell imaging combined with dedicated computation tools, we demonstrate simultaneous 3D single particle localization and tracking of multiple distinct species over large field of views to be feasible without compromising spatio-temporal resolution. The dispersive element introduced into the second optical path induces a spectrally dependent displacement, which we used to analytically separate up to five different fluorescent species of single emitters based on their emission spectra. We used commercially available microscope bodies aligned one on top of the other, offering biologists with a very ergonomic and flexible instrument covering a broad range of SMLM applications. Finally, we developed a powerful freely available software, called PALMTracer, which allows to quantitatively assess 3D + t + λ SMLM data. We illustrate the capacity of our approach by performing multi-color 3D DNA-PAINT of fixed samples, and demonstrate simultaneous tracking of multiple receptors in live fibroblast and neuron cultures.
Multi-dimensional spectral Single Molecule Localization Microscopy
Authors: Corey Butler, G. Ezequiel Saraceno, Adel Kechkar, Vincent Studer, Julien P. Dupuis, Laurent Groc, Rémi Galland, Jean-Baptiste Sibarita
Front. Bioinform., 04 March 2022 | https://doi.org/10.3389/fbinf.2022.813494
+ Cf. Bordeaux Neurocampus website here
2022-03-03 (MULLE Team) : Awarded 2022 Prize for Innovation of the Académie des Sciences et Belles Lettres de Bordeaux
Valérie Crépel (INSERM) at the University of Aix-Marseille and Christophe Mulle (CNRS) at the Interdisciplinary Institute for Neuroscience at the University of Bordeaux have been awarded the 2022 Prize for Innovation of the Académie des Sciences et Belles Lettres de Bordeaux.
Valérie Crépel and Christophe Mulle are very high-level researchers interested in the physiology and pathology of the hippocampus circuits, a region of the brain located in the temporal lobes, which is the seat of memory and learning.
Their highly innovative research focuses on the therapeutic approach to the treatment of temporal lobe epilepsy. This pathology affects 1.3 million people in Europe and the United States, including 800,000 patients who are resistant to known treatments. Christophe Mulle and Valérie Crépel propose gene therapy as an alternative to surgery and its drawbacks. Their therapeutic proposal is developed within Corlieve Therapeutics: it uses microRNA technology, nucleic acids capable of acting at the level of messenger RNA to selectively reduce aberrant effects in the hippocampus of patients.
2022-01-28 (MULLE Team) : APP accumulates with presynaptic proteins around amyloid plaques: a key feature in Alzheimer disease
In Alzheimer's disease (AD), the distribution of the amyloid precursor protein (APP) and its fragments other than amyloid beta, has not been fully characterized. Here, we investigate the distribution of APP and its fragments in human AD brain samples and in mouse models of AD in reference to its proteases, synaptic proteins, and histopathological features characteristic of the AD brain, by combining an extensive set of histological and analytical tools. We report that the prominent somatic distribution of APP observed in control patients remarkably vanishes in human AD patients to the benefit of dense accumulations of extra-somatic APP, which surround dense-core amyloid plaques enriched in APP-Nter. These features are accentuated in patients with familial forms of the disease. Importantly, APP accumulations are enriched in phosphorylated tau and presynaptic proteins whereas they are depleted of post-synaptic proteins suggesting that the extra-somatic accumulations of APP are of presynaptic origin. Ultrastructural analyses unveil that APP concentrates in autophagosomes and in multivesicular bodies together with presynaptic vesicle proteins. Altogether, alteration of APP distribution and its accumulation together with presynaptic proteins around dense-core amyloid plaques is a key histopathological feature in AD, lending support to the notion that presynaptic failure is a strong physiopathological component of AD.
APP accumulates with presynaptic proteins around amyloid plaques: a role for presynaptic mechanisms in Alzheimer’s disease?
Authors: Tomàs Jordà-Siquier, Melina Petrel, Vladimir Kouskoff, Una Smailovic, Fabrice Cordelières, Susanne Frykman, Ulrike Müller, Christophe Mulle, Gaël Barthet
Alzheimer's & Dementia, The Journal of the Alzheimer's Association - 25 January 2022 DOI: 10.1002/alz.12546
2021-11-19 (CHOQUET Team) : 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
2021-11-08 (GIANNONE Team) : Mechanical control of actin regulators during cell migration - Nature Cell Biology, Nov. 2021
Actin filaments generate mechanical forces that drive membrane movements during trafficking, endocytosis and cell migration. Reciprocally, adaptations of actin networks to forces regulate their assembly and architecture. Yet, a demonstration of forces acting on actin regulators at actin assembly sites in cells is missing. Here we show that local forces arising from actin filament elongation mechanically control WAVE regulatory complex (WRC) dynamics and function, that is, Arp2/3 complex activation in the lamellipodium. Single-protein tracking revealed WRC lateral movements along the lamellipodium tip, driven by elongation of actin filaments and correlating with WRC turnover. The use of optical tweezers to mechanically manipulate functional WRC showed that piconewton forces, as generated by single-filament elongation, dissociated WRC from the lamellipodium tip. WRC activation correlated with its trapping, dwell time and the binding strength at the lamellipodium tip. WRC crosslinking, hindering its mechanical dissociation, increased WRC dwell time and Arp2/3-dependent membrane protrusion. Thus, forces generated by individual actin filaments on their regulators can mechanically tune their turnover and hence activity during cell migration.
Authors: Amine Mehidi, Frieda Kage, Zeynep Karatas, Maureen Cercy, Matthias Schaks, Anna Polesskaya, Matthieu Sainlos, Alexis Gautreau, Olivier Rossier, Klemens Rottner and Grégory Giannone
Forces generated by lamellipodial actin filament elongation regulate the WAVE complex during cell migration
Nature Cell Biology, 23, pages 1148–1162 (2021). https://www.nature.com/articles/s41556-021-00786-8
*Contact IINS: Grégory Giannone
2021-09-13 (PERRAIS Team) : Post-synaptic exocytosis and synaptic plasticity - Cell Reports Sept 2021
Synapses, the basic building blocks of neural networks, are both very stable and capable of rapid and long-lasting modifications, a phenomenon known as synaptic plasticity. The modification of a synapse often involves the addition of synaptic receptors (long-term potentiation or LTP) or the removal of part of the synaptic receptors (long-term depression or LTD). This rapid plasticity is possible because synaptic receptors are not immobile in the synapse but travel to intracellular compartments called recycling endosomes (RE). The regulation of RE trafficking has thus become an important topic of study for understanding the mechanisms of synaptic plasticity.
Picture of all contributors of this study. David Perrais and May Bakr stand in front of "The paint pipette", taken by May, which was awarded the best IINS picture prize in 2020.
In this study, we searched for the molecules involved in these phenomena, in particular the proteins responsible for exocytosis called SNAREs. The VAMP2 protein, target of the tetanus toxin (released by the bacterium responsible for tetanus and one of the most deadly in humans), was known to block LTP. However, to our surprise, it only marginally affected RE exocytosis. We therefore searched for other SNARE proteins and found VAMP4 to be responsible for the majority of RE exocytosis, whereas VAMP2 is involved in only a small fraction of exocytosis, but plays a major role in the exocytosis of REs containing AMPA-type postsynaptic receptors (see Figure). Furthermore, VAMP4 deletion also alters the trafficking of AMPA receptors that are in greater quantity at the surface of neurons, increasing synaptic transmission and limiting its plasticity by occlusion.
This work shows the great diversity of membrane trafficking mechanisms in the dendrites of neurons that allows receptors to be delivered when and where they are needed to regulate individual synapses. It was the result of a long-term work, over more than eight years, of many students, engineers and researchers of the IINS.
2021-09-07 (MULLE Team) : Celebrating the sale of Corlieve Therapeutics
Happy to celebrate the sale of Corlieve Therapeutics for 250 M€, the startup created by Christophe Mulle and Valérie Crépel from their work partly at IINS.
Corlieve Therapeutics is a biotechnology company focused on bringing novel therapeutic options to patients with severe neurological disorders. The lead project is targeting aberrantly expressed kainate receptors in the hippocampus of patients with refractory Temporal Lobe Epilepsy using a gene therapy approach.
More info here
2021-09-03 (ROUX Team) : Lisa gave a talk at the 3rd Science and Gender Equality Symposium “SAGE 3.0”
Dates: October 21-22, 2021 on ZOOM. The symposium is funded by the DFG Collaborative Research Center 936 (SFB 936). To know more, follow the link below.
2021-08-30 (ROUX Team) : Lisa Roux laureate of the Fondation Schlumberger pour l'Education et la Recherche
The Schlumberger Foundation for Education and Research selects each year three laureates amongst the best young researchers who are building their team in the field of life sciences. A group leader of IINS, Lisa Roux, is one of the laureates in 2021. She has just received a prize to support the establishment of her team and will join the Cercle FSER in taking action to defend and highlight the value of basic science research.
2021-08-30 (ROUX Team) : Evan Harrell is joining the team with an IdEx Junior Chair of Bordeaux University
Congratulations to him!
2021-05-25 (GIANNONE Team) : Orré T., Rossier O. and Giannone G. in Nature Communications - May 2021
Focal adhesions (FAs) initiate chemical and mechanical signals involved in cell polarity, migration, proliferation and differentiation. Super-resolution microscopy revealed that FAs are organized at the nanoscale into functional layers from the lower plasma membrane to the upper actin cytoskeleton. Yet, how FAs proteins are guided into specific nano-layers to promote interaction with given targets is unknown. Using single protein tracking, super-resolution microscopy and functional assays, we link the molecular behavior and 3D nanoscale localization of kindlin with its function in integrin activation inside FAs. We show that immobilization of integrins in FAs depends on interaction with kindlin. Unlike talin, kindlin displays free diffusion along the plasma membrane outside and inside FAs. We demonstrate that the kindlin Pleckstrin Homology domain promotes membrane diffusion and localization to the membrane-proximal integrin nano-layer, necessary for kindlin enrichment and function in FAs. Using kindlin-deficient cells, we show that kindlin membrane localization and diffusion are crucial for integrin activation, cell spreading and FAs formation. Thus, kindlin uses a different route than talin to reach and activate integrins, providing a possible molecular basis for their complementarity during integrin activation.
2021-05-14 (CHOQUET Team) : 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.
2021-04-16 (GROC Team) : Moissons d'avril 2021
Groc team students have been awarded for the Bordeaux University festival "Moissons d'avril" to give a "visio"concert...
2021-04-12 (NAGERL Team) : On the cover: Neuron - astrocyte interactions - Glia, June 2021 issue
Super‐resolution shadow imaging reveals local remodeling of astrocytic microstructures and brain extracellular space after osmotic challenge
The extracellular space (ECS) plays a central role in brain physiology, shaping the time course and spread of neurochemicals, ions, and nutrients that ensure proper brain homeostasis and neuronal communication. Astrocytes are the most abundant type of glia cell in the brain, whose processes densely infiltrate the brain's parenchyma. As astrocytes are highly sensitive to changes in osmotic pressure, they are capable of exerting a potent physiological influence on the ECS. However, little is known about the spatial distribution and temporal dynamics of the ECS that surrounds astrocytes, owing mostly to a lack of appropriate techniques to visualize the ECS in live brain tissue. Mitigating this technical limitation, we applied the recent SUper‐resolution SHadow Imaging technique (SUSHI) to astrocyte‐labeled organotypic hippocampal brain slices, which allowed us to concurrently image the complex morphology of astrocytes and the ECS with unprecedented spatial resolution in a live experimental setting. Focusing on ring‐like astrocytic microstructures in the spongiform domain, we found them to enclose sizable pools of interstitial fluid and cellular structures like dendritic spines. Upon experimental osmotic challenge, these microstructures remodeled and swelled up at the expense of the pools, effectively increasing the physical interface between astrocytic and cellular structures. Our study reveals novel facets of the dynamic microanatomical relationships between astrocytes, neuropil, and the ECS in living brain tissue, which could be of functional relevance for neuron–glia communication in a variety of (patho)physiological settings, for example, LTP induction, epileptic seizures or acute ischemic stroke, where osmotic disturbances are known to occur.
2021-03-16 (ROUX Team) : Lisa interviewed for article in Horizon Magazine
On the role of social scents. Article by Alex Whiting.
2021-03-16 (ROUX Team) : Lisa and Pascal contributed to "L'Enquête des Sens"
Chaque année, les étudiant·es du master Médiation des sciences de Bordeaux et l’association Dealers de Sciences organisent une semaine de culture scientifique et technique. Pour sa 5ème édition, la thématique choisie est « L’Enquête des Sens ». Lisa Roux et Pascal Ravassard ont répondu aux questions de leur interviewers sur la perception olfactive (https://www.lenquetedessens.dealersdescience.com/index.php/2020/10/03/les-serrures-de-lodorat/) et le lien entre mémoire et odorat (https://www.lenquetedessens.dealersdescience.com/index.php/2020/11/08/les-echos-de-la-memoire/).
2021-03-15 : Brain Week 2021
The 23rd Brain Week takes place from March 15 to 22, 2021.
Several online events are proposed by the Neuroscience Bordeaux community.
Find the events organized locally on the websites of Bordeaux Neurocampus and Société des neurosciences and visit the scientific image exhibition created by IINS. Find the best pictures from IINS members with their legends.
Follow this link : https://neuro-extramuros.u-bordeaux.fr/CERVEAU2021/
2021-03-14 (CHOQUET Team) : 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.
2021-02-23 (GAMBINO Team) : Dendritic spikes and cortical remapping, PNAS February 2021
An increase in dendritic plateau potentials is associated with experience-dependent cortical map reorganization
2021-01-14 (PERRAIS Team) : MemTraS Team crew is expanding
We are pleased to welcome several new members:
Sarka Jelinkova - Post Doctoral Fellow - Expert in Stem cell biology and molecular biology - Ph.D U Brno - Czech Republic
Nathan Hoareau - Master 2 rotation student - Ecole Supérieure de Chimie Organique et Minerale
Juan Manuel Defauce Garcia - Master 1 NeuroBIM rotation student - Université de Bordeaux
Khadija Inam - Master 1 NeuroBIM rotation student - Université de Bordeaux
Fantine Morinière - Technician degree rotation student - BTS Biotechnologies - Lycée Saint-Louis - Bordeaux
Welcome to all of them!
2021-01-13 (MULLE Team) : The relationship between brain state and membrane potential in CA3 pyramidal cells
Wakefulness is comprised of distinct brain states correlated with different behaviors and stages of memory. It is hypothesized that memory encoding and recall are more prominent during active behaviors, while memory consolidation is more prominent during rest. The hippocampal region of the brain is involved in all these stages of memory during their respective brain states. For this brain circuit to perform these different computations at different times, it has been hypothesized that the membrane potential of individual neurons must change in a brain state-dependent manner. We sought to test this hypothesis by recording membrane potential from individual CA3 hippocampal pyramidal cells in awake mice during active and restful behaviors. When animals are actively moving, the hippocampal local field potential displays a 4-12 Hz oscillation known as theta. We found that, consistent with the hypothesis, CA3 pyramidal cells underwent consistent changes in membrane potential when theta was present in the local field potential. Specifically, these cells hyperpolarized, decreased firing, and had low membrane potential variance, all of which are consistent with increased inhibition. This sustained, coherent suppression of CA3 pyramidal cells during theta likely changes the circuit dynamics within the hippocampus, contributing to a functional switch that might underlie the ability of the hippocampus to participate in memory encoding during theta.
- Cell Reports 2020 - doi: 10.1016/j.celrep.2020.107868
- Authors and contacts: Meryl Malezieux, Ashley L Kees and Christophe Mulle
+ Cf Bordeaux Neurocampus website here
2021-01-06 (STUDER Team) : "Cell Organ-izers”, a new IINS and Alvéole LabCom
Faced with the same challenges for their academic research work or their clients needs, the IINS group led by Vincent Studer “Organ-izing the cell” and Alvéole have decided to create a common laboratory "Cell Organ_izers". It will aim at establishing a tight research partnership, likely to have a leverage effect in terms of both scientific production and innovation. The general theme of research of the JRL will be the development of scale up tools and methods to craft standardized human in vitro models for biology with the general goal of reconciliating the simplicity of in vitro models with complex properties encountered in vivo. We will focus our investigations on tools, methods and principles in straight line with Alveole’s product line, patent portfolio and target market. The results that we have obtained together within our previous collaboration contracts will be the starting bricks of the program.
Contact: vincent.studer at u-bordeaux.fr
+ See the Bordeaux Neurocampus website here
2021-01-05 (NAGERL Team) : Award of ERC Synergy Grant
Together with my Bordeaux colleagues (E. Bezard, L. Cognet and L. Groc), I am a proud recipient of an ERC Synergy grant from the EU, which supports high-risk/high gain frontier research in Europe. This is a tremendous recognition of our work, which will give us resources and wings to conduct some cool and ground-breaking research in the years to come! I am extremely grateful to all the members of my team and collaborators who have contributed to this success over the years and made it possible.
2020-11-19 (THOUMINE Team) : FluoSim, Matthieu Lagardère and Olivier Thoumine in Scientific Reports - November 2020
We introduce fast, robust, and user-friendly software called FluoSim that allows for real time simulation of membrane protein dynamics in live-cell imaging and super-resolution modalities. We also show that FluoSim can be used to produce large virtual data sets for training deep neural networks for image reconstruction. This software should thus be of great interest to a wide community specialized in imaging methods applied to cell biology and neuroscience, with the common aim to better understand membrane dynamics and organization in cells. FluoSim is freely available on the website of the publisher Scientific Reports.
FluoSim: simulator of single molecule dynamics for fluorescence live-cell and super-resolution imaging of membrane proteins
- Authors: Lagardère M, Chamma I, Bouilhol E, Nikolski M, Thoumine
- Scientific Reports 10, 19954 (2020). https://doi.org/10.1038/s41598-020-75814-y
+ See the movie here
Simulation of a Fluorescence Recovery After Photobleaching (FRAP) experiment.
The movie generated with FluoSim shows the distribution of surface receptors in a dendritic segment, with specific accumulation in post-synaptic areas (red color).
Receptors are photobleached at t = 5 sec in two specific synapses. Note the fluorescence recovery over time (total 60 sec), due to receptor diffusion and turnover.
2020-11-05 : IINS teams awarded a prestigious ERC Synergy 2020
Congratulations to our ERC synergy 2020 awardees L. Groc, E. Bézard, V. Nägerl and L. Cognet!
We are happy and proud of this selection that will further expand our knowledge of the properties and function of the Brain extracellular space.
The teams of Laurent Groc (Research Director CNRS; Interdisciplinary Institute for Neuroscience), Erwan Bézard (Research Director Inserm; Institute of Neurodegenerative Disorders), Laurent Cognet (Research Director CNRS; Laboratoire photonique numérique et nanosciences) and Valentin Nägerl (Professor at University of Bordeaux; Interdisciplinary Institute for Neuroscience) have been awarded the ERC Synergy Award 2020. The ENSEMBLE project aims at underpinning the molecular mechanisms of physiological and pathological brain function. This ambitious and innovative endeavor is based on their ability to develop new approaches in high-resolution microscopy at the service of a new conceptual framework in brain cell communication.
This project has roots in the international leadership of the Bordeaux community in the fields of microscopy, nanophotonics, fundamental and translational neuroscience. The opportunity that is offered to these 4 investigators to break a frontier knowledge was permitted by the continuous support of local institutional actors. The installation of Prof. Valentin Nägerl’s laboratory in 2009 with a "Chaire Accueil" from the Regional Council of Nouvelle-Aquitaine, the support of LabEx BRAIN, the Laphia Cluster and the IdEx of the University of Bordeaux provided the ground to build elementary blocks necessary for the challenging adventure of the ERC Synergy project (10 million euros, 6 years).
2020-10-23 (TAKAHASHI Team) : Nature Neuroscience, October 2020 cover
Nature Neuroscience has selected the Naoya Takahashi's last paper 'Active dendritic currents gate descending cortical outputs in perception' for his October 2020 volume cover.
2020-10-22 (STUDER Team) : Microfabrication - Advanced Healthcare Materials, Oct. 2020
Physiologically relevant cell‐based models require engineered microenvironments which recapitulate the topographical, biochemical, and mechanical properties encountered in vivo. In this context, hydrogels are the materials of choice. Here a light based toolbox is able to craft such microniches out of common place materials. Extensive use of benzophenone photoinitiators and their interaction with oxygen achieves this. First, the oxygen inhibition of radicals is harnessed to photoprint hydrogel topographies. Then the chemical properties of benzophenone are exploited to crosslink and functionalize native hydrogels lacking photosensitive moieties. At last, photoscission is introduced: an oxygen driven, benzophenone‐enabled reaction that photoliquefies Matrigel and other common gels. Using these tools, soft hydrogel templates are tailored for cells to grow or self organize into standardized structures. The described workflow emerges as an effective microniche manufacturing toolset for 3D cell culture.
+ Thumbnail Leg. This spheroidally shaped cell culture of human embryonic kidney cells was templated by a photochemical technique. Vincent Studer and co-workers used photochemistry to controllably create hollow shapes within hydrogel structures. These hollows were then seeded with cells, which grew to fill the empty space. The spheroids were stained using a cell marker and the 3D imaging was accomplished with a bespoke digital micromirror-device-based confocal microscope.
2020-10-05 : Naoya Takahashi, laureate of the ATIP-Avenir 2020
Every year, as part of a partnership, Inserm and the French National Center for Scientific Research (CNRS) launch a call for proposals aimed at enabling young researchers to create and lead a team within an established Inserm or CNRS research center. The teams formed will work to strengthen the research of the host unit by independently developing their own research projects. This program aims to promote mobility and attract young, high-caliber team leaders.
Contact: Naoya Takahashi
2020-09-26 (NAGERL Team) : Nanoscale remodeling of astroglial processes
Extrasynaptic actions of glutamate are limited by high-affinity transporters expressed by perisynaptic astroglial processes (PAPs): this helps maintain point-to-point transmission in excitatory circuits. Memory formation in the brain is associated with synaptic remodeling, but how this affects PAPs and therefore extrasynaptic glutamate actions is poorly understood. Here, we used advanced imaging methods, in situ and in vivo, to find that a classical synaptic memory mechanism, long-term potentiation (LTP), triggers withdrawal of PAPs from potentiated synapses. Optical glutamate sensors combined with patch-clamp and 3D molecular localization reveal that LTP induction thus prompts spatial retreat of astroglial glutamate transporters, boosting glutamate spillover and NMDA-receptor-mediated inter-synaptic cross-talk. The LTP-triggered PAP withdrawal involves NKCC1 transporters and the actin-controlling protein cofilin but does not depend on major Ca2+-dependent cascades in astrocytes. We have therefore uncovered a mechanism by which a memory trace at one synapse could alter signal handling by multiple neighboring connections.
Christian Henneberger et al in Neuron (2020)
2020-09-26 (CHOQUET Team) : Multicolor Spectrin labeling (ML Jobin)
This is a rat hippocampal neuron in culture stained with a series of markers
2020-09-22 : Synaptic plasticity and the recovery of altered skills
AMPAR-Dependent Synaptic Plasticity Initiates Cortical Remapping and Adaptive Behaviors during Sensory Experience
Cortical plasticity improves behaviors and helps recover lost functions after injury. However, the underlying synaptic mechanisms remain unclear. In mice, we show that trimming all but one whisker enhances sensory responses from the spared whisker in the barrel cortex and occludes whisker-mediated synaptic potentiation (w-Pot) in vivo. In addition, whisker-dependent behaviors that are initially impaired by single-whisker experience (SWE) rapidly recover when associated cortical regions remap. Cross-linking the surface GluA2 subunit of AMPA receptors (AMPARs) suppresses the expression of w-Pot, presumably by blocking AMPAR surface diffusion, in mice with all whiskers intact, indicating that synaptic potentiation in vivo requires AMPAR trafficking. We use this approach to demonstrate that w-Pot is required for SWE-mediated strengthening of synaptic inputs and initiates the recovery of previously learned skills during the early phases of SWE. Taken together, our data reveal that w-Pot mediates cortical remapping and behavioral improvement upon partial sensory deafferentation.
Authors: Tiago Campelo, Elisabete Augusto, Nicolas Chenouard, Come Camus, Daniel Choquet, Frédéric Gambino
2020-09-21 (GROC Team) : NMDA receptor along dendrites - PNAS, September 2020
Hippocampal pyramidal neurons are characterized by a unique arborization subdivided in segregated dendritic domains receiving distinct excitatory synaptic inputs with specific properties and plasticity rules that shape their respective contributions to synaptic integration and action potential firing. Although the basal regulation and plastic range of proximal and distal synapses are known to be different, the composition and nanoscale organization of key synaptic proteins at these inputs remains largely elusive. Here we used superresolution imaging and single nanoparticle tracking in rat hippocampal neurons to unveil the nanoscale topography of native GluN2A- and GluN2B-NMDA receptors (NMDARs) -which play key roles in the use-dependent adaptation of glutamatergic synapses- along the dendritic arbor. We report significant changes in the nanoscale organization of GluN2B-NMDARs between proximal and distal dendritic segments, whereas the topography of GluN2A-NMDARs remains similar along the dendritic tree. Remarkably, the nanoscale organization of GluN2B-NMDARs at proximal segments depends on their interaction with calcium/calmodulin-dependent protein kinase II (CaMKII), which is not the case at distal segments. Collectively, our data reveal that the nanoscale organization of NMDARs changes along dendritic segments in a subtype-specific manner and is shaped by the interplay with CaMKII at proximal dendritic segments, shedding light on our understanding of the functional diversity of hippocampal glutamatergic synapses.
Authors: Joana S. Ferreira, Julien P. Dupuis, Blanka Kellermayer, Nathan Bénac, Constance Manso, Delphine Bouchet, Florian Levet, Corey Butler, Jean-Baptiste Sibarita, and Laurent Groc
2020-09-01 (ELEGHEERT Team) : Synthetic excitatory synaptic organizer - Science, August 2020
A synthetic synaptic organizer protein restores glutamatergic neuronal circuits
The human brain contains trillions of synapses within a vast network of neurons. Synapse remodeling is essential to ensure the efficient reception and integration of external stimuli and to store and retrieve information. Building and remodeling of synapses occurs throughout life under the control of synaptic organizer proteins. Errors in this process can lead to neuropsychiatric or neurological disorders. Suzuki et al. combined structural elements of natural synaptic organizers to develop an artificial version called CPTX, which has different binding properties (see the Perspective by Salinas). CPTX could act as a molecular bridge to reconnect neurons and restore excitatory synaptic function in animal models of cerebellar ataxia, familial Alzheimer’s disease, and spinal cord injury. The findings illustrate how structure-guided approaches can help to repair neuronal circuits.
Authors: Kunimichi Suzuki, Jonathan Elegheert, Inseon Song, Hiroyuki Sasakura, Oleg Senkov, Keiko Matsuda, Wataru Kakegawa, Amber J. Clayton, Veronica T. Chang, Maura Ferrer-Ferrer, Eriko Miura, Rahul Kaushik, Masashi Ikeno, Yuki Morioka, Yuka Takeuchi, Tatsuya Shimada, Shintaro Otsuka, Stoyan Stoyanov, Masahiko Watanabe, Kosei Takeuchi, Alexander Dityatev, A. Radu Aricescu, Michisuke Yuzaki
2020-07-30 (GIANNONE Team) : Deciphering mechano-biology using super-resolution microscopy
Cell stretching is amplified by active actin remodeling to deform and recruit proteins in mechano-sensitive structures Detection and conversion of mechanical forces into biochemical signals control cell functions during physiological and pathological processes. Mechano-sensing is based on protein deformations and reorganizations, yet the molecular mechanisms are still unclear. Using a cell stretching device compatible with super-resolution microscopy (SRM) and single protein tracking (SPT), we explored the nanoscale deformations and reorganizations of individual proteins inside mechano-sensitive structures. We achieved SRM after live stretching on intermediate filaments, microtubules and integrin adhesions. Simultaneous SPT and stretching showed that while integrins follow the elastic deformation of the substrate, actin filaments and talin also displayed lagged and transient inelastic responses associated with active acto-myosin remodeling and talin deformations. Capturing acute reorganizations of single-molecule during stretching showed that force-dependent vinculin recruitment is delayed and depends on the maturation of integrin adhesions. Thus, cells respond to external forces by amplifying transiently and locally cytoskeleton displacements enabling protein deformation and recruitment in mechano-sensitive structures.
Authors: Sophie Massou*, Filipe Nunes Vicente*, Franziska Wetzel*, Amine Mehidi, Dan Strehle, Cecile Leduc, Raphaël Voituriez, Olivier Rossier, Pierre, Nassoy and Gregory Giannone
* First co-authors
2020-07-20 : A new website for the Aquitaine Delegation of the CNRS
On the new Aquitaine Delegation website find dedicated pages to the organization of the Delegation, scientific potential, innovation, as well as an agenda and a News section here
2020-07-10 (MULLE Team) : Presynaptic failure in Alzheimer’s disease
Synaptic loss is the best correlate of cognitive deficits in Alzheimer’s disease (AD). Extensive experimental evidence also indicates alterations of synaptic properties at the early stages of disease progression, before synapse loss and neuronal degeneration. A majority of studies in mouse models of AD have focused on post-synaptic mechanisms, including impairment of long-term plasticity, spine structure and glutamate receptor-mediated transmission. Here we review the literature indicating that the synaptic pathology in AD includes a strong presynaptic component. We describe the evidence indicating presynaptic physiological functions of the major molecular players in AD. These include the amyloid precursor protein (APP) and the two presenilin (PS) paralogs PS1 or PS2, genetically linked to the early-onset form of AD, in addition to tau which accumulates in a pathological form in the AD brain. Three main mechanisms participating in presynaptic functions are highlighted. APP fragments bind to presynaptic receptors (e.g. nAChRs and GABAB receptors), presenilins control Ca2+ homeostasis and Ca2+-sensors, and tau regulates the localization of presynaptic molecules and synaptic vesicles. We then discuss how impairment of these presynaptic physiological functions can explain or forecast the hallmarks of synaptic impairment and associated dysfunction of neuronal circuits in AD. Beyond the physiological roles of the AD-related proteins, studies in AD brains also support preferential presynaptic alteration. This review features presynaptic failure as a strong component of pathological mechanisms in AD.
Progress in Neurobiology 2020 - doi:10.1016/j.pneurobio.2020.101801
Authors and contacts: Gaël Barthet and Christophe Mulle
+ Cf Bordeaux Neurocampus website here
2020-07-01 (GROC Team) : 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
2020-06-28 (CHOQUET Team) : 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.
2020-06-08 (CHOQUET Team) : 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
2020-06-08 : Receptor mobility under the spotlight
Linking glutamate receptor movements and synapse function
Regulation of neurotransmitter receptor content at synapses is achieved through a dynamic equilibrium between biogenesis and degradation pathways, receptor stabilization at synaptic sites, and receptor trafficking in and out synapses. In the past 20 years, the movements of receptors to and from synapses have emerged as a series of highly regulated processes that mediate postsynaptic plasticity. Our understanding of the properties and roles of receptor movements has benefited from technological advances in receptor labeling and tracking capacities, as well as from new methods to interfere with their movements. Focusing on two key glutamatergic receptors, we review here our latest understanding of the characteristics of receptor movements and their role in tuning the efficacy of synaptic transmission in health and brain disease.
2020-05-28 (PERRAIS Team) : MemTraS: A new team at IINS
"MemTraS - Membrane traffic at synapses" is a new team recently born at IINS. The leader, David Perrais, presents the research axis:
Our goal in the team is to study the mechanisms of synapse function. We focus on membrane trafficking events, exocytosis and endocytosis, in normal brain physiology or in the course of disease. Indeed, membrane trafficking is essential in both sides of the synapse. The presynaptic element is filled with synaptic vesicles which fuse at the active zone to release neurotransmitter molecules, one of the defining features of synaptic transmission. After fusion, vesicles are very quickly and efficiently recycled to cope with neuronal activity. At the post-synaptic side, post-synaptic receptors are going through cycles of endocytosis and recycling, which is essential to regulate synaptic transmission and plasticity. We want to analyse how these processes are organized in space and time. Finally, we are not only interested in canonical synapses, such as cortical glutamatergic synapses, but also in rare and much less understood synapse populations such as neuromodulatory dopamine synapses.
To tackle these issues, we combine two types of expertise mastered by the researchers of the team, myself and Etienne Herzog. I bring electrophysiology combined with the most advanced fluorescence imaging techniques to detect and characterize individual exocytosis and endocytosis events in living cells, while Etienne brings his method of purification of synaptosomes from adult animals with fluorescence activated synaptosome sorting which enables powerful proteomics, transcriptomics and functional approaches. Altogether we aim at identifying new principles of organization in specific synapses and test their relevance for synaptic function in the normal and diseased brain.
The members of the team being formed in January 2020 are Lou Bouit, Silvia Sposini, Marlene Pfeffer, Etienne Herzog, May Bakr and David Perrais.
- More details on the Bordeaux Neurocampus website here.
- Contact: David Perrais
2020-04-29 (THOUMINE Team) : Controlling synapse differentiation with light - eLife, April 2020
Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation.
Neuroligins (Nlgns) are adhesion proteins mediating trans-synaptic contacts in neurons. However, conflicting results around their role in synaptic differentiation arise from the various techniques used to manipulate Nlgn expression level. Orthogonally to these approaches, we triggered here the phosphorylation of endogenous Nlgn1 in CA1 mouse hippocampal neurons using a photoactivatable tyrosine kinase receptor (optoFGFR1). Light stimulation for 24 hr selectively increased dendritic spine density and AMPA-receptor-mediated EPSCs in wild-type neurons, but not in Nlgn1 knock-out neurons or when endogenous Nlgn1 was replaced by a non-phosphorylatable mutant (Y782F). Moreover, light stimulation of optoFGFR1 partially occluded LTP in a Nlgn1-dependent manner. Combined with computer simulations, our data support a model by which Nlgn1 tyrosine phosphorylation promotes the assembly of an excitatory post-synaptic scaffold that captures surface AMPA receptors. This optogenetic strategy highlights the impact of Nlgn1 intracellular signaling in synaptic differentiation and potentiation, while enabling an acute control of these mechanisms.
Authors: Letellier M, Lagardère M, Tessier B, Janovjak H, Thoumine O.
2020-04-23 (NAGERL Team) : Tripartite synapses: up close & personal with STED microscopy
Astrocytic calcium signals can be fast and local, supporting the idea that astrocytes have the ability to regulate single synapses. However, the anatomical basis of such specific signaling remains unclear, owing to difficulties in resolving the spongiform domain of astrocytes where most tripartite synapses are located. Using 3D-STED microscopy in living organotypic brain slices, we imaged the spongiform domain of astrocytes and observed a reticular meshwork of nodes and shafts that often formed loop-like structures. These anatomical features were also observed in acute hippocampal slices and in barrel cortex in vivo. The majority of dendritic spines were contacted by nodes and their sizes were correlated. FRAP experiments and calcium imaging showed that nodes were biochemical compartments and Ca2+ microdomains. Mapping astrocytic calcium signals onto STED images of nodes and dendritic spines showed they were associated with individual synapses. Here, we report on living nanoscale organization of astrocytes, identifying nodes as a functional astrocytic component of tripartite synapses that may enable synapse-specific communication between neurons and astrocytes.
Misa Arizono et al in Nature Communications (2020)
2020-04-07 : Information : Coronavirus
The French Academy of Sciences provides links to find reliable information on the COVID-19 Coronavirus epidemic.
2020-03-16 : IINS is temporarily closed
Our lab has closed down to allow the personnel to go under confinement and protection. A handful of dedicated members is taking care of our precious biological samples and mouse colonies.
2019-12-05 (CHOQUET Team) : 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