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Cell Adhesion Molecules in Synapse Assembly

Team Leader : Olivier Thoumine

After completing an engineering degree at Ecole Centrale Paris, I carried out my Ph.D. at Georgia Tech (Atlanta), where I studied integrin-dependent mechanotransduction in the response of endothelial cells to hemodynamic forces. During my post-docs at Institut Curie (Paris) and Ecole Polytechnique Fédérale (Lausanne), I designed micromanipulation methods to quantify the response of cells to mechanical deformations. After my recruitment by the CNRS in the team of D. Choquet (Bordeaux), I developed biomimetic systems coupled with high resolution imaging and predictive biophysical models, to probe the role of the cytoskeleton and adhesion proteins in growth cone motility and synaptogenesis. I created an independent team in 2010, focusing on the dynamics and function of synaptic adhesion molecules. The team now oscillates between 10-12 people including permanent researchers, technicians, post-docs, PhD and Master students.

Contact: Olivier Thoumine, tel. +33 (0)5 33 51 47 04; e-mail: Olivier.thoumine@u-bordeaux.fr

 

General objective

Elucidation of the complex map of neural connectivity in the mammalian brain is one of the major goals of neuroscience research. Fundamental to such efforts, and to the comprehension of neurological disorders, is to gain an understanding of the mechanisms that form and maintain synaptic connections. Adhesion proteins play important roles in these processes, not only by establishing a structural linkage between pre- and post-synaptic membranes, but also by instructing the differentiation of synaptic compartments through the connection to specific molecular partners, regulated by signaling mechanisms.

In this context, our team aims at better understanding the role of adhesion molecules in synapse assembly and differentiation, with a focus on specific proteins including N-cadherin, neurexins, neuroligins, LRRTMs, and their associated partners (MDGAs, actin cytoskeleton, scaffolding proteins, glutamate receptors). We are particularly interested in characterizing the membrane dynamics, binding kinetics, nanoscale organization, and signaling mechanisms associated with these molecular complexes. Our working models, both isolated from rodent brains, are dissociated hippocampal neurons which bear good optical properties for super-resolution imaging, and organotypic hippocampal slices that have well-preserved dendritic architecture and synaptic connectivity.

Research Projects

In silico and in vitro methods to quantify interaction dynamics between synaptic proteins

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Regulation of neuroligin-1 dynamics, organization, and function at the synapse

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Molecular mechanisms of excitatory synapse development and nano-organization

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Interplay between cell adhesion molecules and neuronal activity in synaptic circuit dynamics

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Epigenetic and transcriptomic regulation of synaptic adhesion molecules during development and plasticity

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Expertise

  • Computer simulations based on single molecule dynamics
  • Micropatterning assays
  • Nanoprobe development
  • super-resolution microscopy
  • Electrophysiology
  • Optogenetics
  • News

    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.

    - Publication on Elife. 2020 Apr 23;9. pii: e52027. doi: 10.7554/eLife.52027.
    - Contacts: Mathieu Letellier and Olivier Thoumine
    + Cf Bordeaux Neurocampus website here

    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

    Movie Legend:
    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.

    Selected Publications

  • Letellier M., Lagardère M., Tessier B., Janovjak H., Thoumine, O.
  • Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation eLife (2020)
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  • Lagardère M., Chamma I., Bouilhol E., Nikolski M., Thoumine O.
  • FluoSim: simulator of single molecule dynamics for fluorescence live-cell and super-resolution imaging of membrane proteins Scientific Reports (2020)
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  • Ingrid Chamma & Olivier Thoumine
  • Dynamics, nanoscale organization, and function of synaptic adhesion molecules Molecular and Cellular Neuroscience (2018)
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  • Letellier M, Sziber Z, Chamma I, Saphy C, Papasideri I, Tessier B, Sainlos M, Czöndor K, Thoumine O
  • A unique intracellular tyrosine in neuroligin-1 regulates AMPA receptor recruitment during synapse differentiation and potentiation. Nature Communications (2018)
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  • Chamma I, Rossier O, Giannone G, Thoumine O, Sainlos M.
  • Optimized labeling of membrane proteins for applications to super-resolution imaging in confined cellular environments using monomeric streptavidin Nature Protocols (2017)
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  • Ingrid Chamma, Mathieu Letellier, Corey Butler, Béatrice Tessier, Kok-Hong Lim, Isabel Gauthereau, Daniel Choquet, Jean-Baptiste Sibarita, Sheldon Park, Matthieu Sainlos* & Olivier Thoumine*
  • Mapping the dynamics and nanoscale organization of synaptic adhesion proteins using monomeric streptavidin Nature Communications (2016)
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  • Mathieu Letellier, Sara Elramah, Magali Mondin, Anaïs Soula, Andrew Penn, Daniel Choquet, Marc Landry, Olivier Thoumine & Alexandre Favereaux
  • miR-92a regulates expression of synaptic GluA1-containing AMPA receptors during homeostatic scaling Nature Neuroscience (2014)
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    Members

    « Researcher »

    CHAMMA Ingrid Researcher ingrid.chamma@u-bordeaux.fr +33533514729
    FAVEREAUX Alexandre Researcher alexandre.favereaux@u-bordeaux.fr +33533514763
    LETELLIER Mathieu Researcher mathieu.letellier@u-bordeaux.fr +33533514729
    THOUMINE Olivier Researcher olivier.thoumine@u-bordeaux.fr +33533514704

    « Technical Staff »

    MUNIER Matthieu Technical staff matthieu.munier@u-bordeaux.fr +33533514749
    TESSIER Beatrice Technical staff beatrice.tessier@u-bordeaux.fr +33533514729

    « Postdoc »

    MCKENZIE Catherine Postdoc catherine.mckenzie@u-bordeaux.fr
    TOLEDO Andrea Postdoc andrea.toledo@u-bordeaux.fr +33533514729

    « PhD student »

    GASSAMA Yadaly PhD student yadaly.gassama@u-bordeaux.fr +33533514700
    LIOUTA Konstantina PhD student konstantina.liouta@etu.u-bordeaux.fr +33533514749