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 8-12 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.email@example.com
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.
In silico and in vitro methods to quantify interaction dynamics between synaptic proteinsMORE
Regulation of neuroligin 1 dynamics organization and function at the synapseMORE
Interplay between cell adhesion molecules and neuronal activity in synaptic circuit dynamicsMORE
Epigenetic and transcriptomic regulation of synaptic adhesion molecules during development and plasticityMORE
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.
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.
Synaptic tagging: homeostatic plasticity goes Hebbian - EMBO Journal, Sept. 2022
Adapting and staying stable: how neurons modify their connections without compromising their functional integrity
A study conducted under the direction of Mathieu Letellier at the IINS, in the team of Olivier Thoumine and in collaboration with Alexandre Favereaux, reveals a molecular mechanism for homeostatic plasticity in which individual neuronal connections, the “synapses”, compensate for prolonged decrease in neuronal activity by increasing the number of glutamate receptors. This study is published in the EMBO Journal.
miR ‐124‐dependent tagging of synapses by synaptopodin enables input‐specific homeostatic plasticity.
Sandra Dubes, Anaïs Soula, Sébastien Benquet, Béatrice Tessier, Christel Poujol, Alexandre Favereaux, Olivier Thoumine, Mathieu Letellier
The EMBO Journal. 2022-07-25 - 10.15252/embj.2021109012
Synaptic tagging: homeostatic plasticity goes Hebbian
Colameo D, Schratt G. EMBO J. 2022 Sep 13:e112383. doi: 10.15252/embj.2022112383. Online ahead of print. PMID: 36097740
Mathieu Letellier, IINS CNRS researcher
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« Technical Staff »
|CHAUVINEAU Benjamin||Technical firstname.lastname@example.org||+33533514700|
|CLOATRE Tiffany||Technical email@example.com||+33533514700|
|DESQUINES Chloé||Technical firstname.lastname@example.org||+33533514700|
|FRANCO Lucie||Technical email@example.com||+33533514700|
|ROUGLAN Vanessa||Technical firstname.lastname@example.org||+33533514700|
|TESSIER Beatrice||Technical email@example.com||+33533514729|
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« PhD student »
|BAZ BADILLO Elena||PhD firstname.lastname@example.org||+33533514700|
|DROUET Adèle||PhD email@example.com||+33533514700|
We are hiring one highly motivated postdoctoral scientist to investigate the molecular, structural and functional organization of the glutamatergic tripartite synapse. In light of recent evidence that astrocytes are not just a mere "glue" surrounding neurons but actively regulate synaptic connections, we want to investigate the molecular interactions that drive and maintain astrocytic processes in close contact with neurons and how those interactions dynamically regulate the structure and plasticity of synapses. To address this question, we will combine whole patch-clamp recordings with single-cell RNA seq (“patch-seq”), proteomics, electrophysiology, expansion microscopy and live microscopy in the mouse hippocampus, where the role of astrocytes in synaptic plasticity is well established. We will further assess the impact of autistic mutations targeting astrocytic protein candidates that have been so far considered only from a neurocentric point of view.
For this project, the candidate should have expertise in either patch-clamp electrophysiology or microscopy and show strong interest in molecular and cellular neuroscience with a focus on neurotransmission and synaptic plasticity. The project is to be developed in the team Cell Adhesion Molecules in Synapse Assembly at IINS of the Bordeaux Neurocampus. The position has 2 years initial funding from ANR.
Candidates should send a CV, a brief statement of research experience and reference letters to Mathieu Letellier: firstname.lastname@example.org