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.firstname.lastname@example.org
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
Portrait of Mathieu Letellier who receives the CNRS 2023 bronze medal
Mathieu Letellier is a CNRS researcher in Olivier Thoumine’s team "Cell Adhesion Molecules in Synapse Assembly” part of the IINS. For many years, he has been interested in the processes that control the plasticity and development of neural connections. His work has highlighted the role of adhesion proteins and neuronal activity in the functional and molecular differentiation of synapses and in the mechanisms of plasticity and homeostasis of neuronal circuits. Recently, Mathieu Letellier was awarded a CNRS 2023 bronze medal.
What is your background?
"I have a background in cell biology and physiology through my undergraduate studies at University Pierre and Marie in Paris. Then I did my graduate studies in the laboratory ‘Neurobiology of Adaptive Processes’ with Pr Jean Mariani and Dr Ann Lohof. Finally, I joined Dr Yukiko Goda as a post-doctoral fellow, first at University College London and then at the RIKEN Brain Science Institute in Tokyo. Overall, through my academic career, I have developed a cell physiologist profile [...] and I am now expanding my skills with molecular approaches and high resolution microscopy."
Why did you choose neuroscience?
"Throughout my studies, I was fortunate to have excellent teachers. They passed on me their passion for neuroscience and the will to better understand how the brain works. Moreover, I have chosen neurosciences owing to their interdisciplinary nature. They catalyse strong interactions between people coming from various backgrounds that include cell biology as well as oncology, immunology […] but also chemistry, physics, mathematics, psychology, ethology and many more!"
"I joined IINS in 2012 following my post-doctorate. At the time, I was looking for a laboratory that would allow me to pursue my research on the development and function of neuronal connections while expanding my field of expertise and knowledge. IINS appeared to be an excellent option: a laboratory in full effervescence, very attractive, open to the world and marked by interdisciplinarity! In addition to that, I had the opportunity to join Olivier Thoumine’s team in which I later obtained a permanent CNRS position. In my opinion, this team perfectly illustrates the spirit of the IINS. Indeed, every members brings a different expertise."
Can you tell us about your research?
"My research has two goals. The first one is to understand how neurons form connections (or synapses) between themselves. The second is to identify the mechanisms by which they modify those connections, either by strengthening or weakening them, to adapt the brain to its environment. These objectives are hampered by the fact that each single neuron harbours a very large number of synapses (10,000 on average) displaying high molecular and functional diversity […]. In the past years, I have been interested in the role of a cell adhesion protein called ‘neuroligin’, whose function is to connect neurons to each other. On the other hand, some mutations in the ‘neuroligin’ genes are associated with autism. In the team, we have shown that the phosphorylation of this protein plays an important role in the differentiation of excitatory synapses but also in long-term synaptic plasticity, the subcellular substrate for learning and memory.”
You have just been awarded the CNRS Bronze Medal 2023. What does this award mean to you?
"To quote the CNRS, this medal ‘rewards the first achievements of researchers who are specialists in their field’. I am beyond honoured to receive this award. In my eyes, it represents: ‘an incentive from the CNRS to continue my research.’ Although this medal is awarded individually, it rewards work in which many people have participated. I thus owe it to my mentors and colleagues I have met and worked with throughout my career, particularly at IINS and within my team."
An advice for young researchers?
"What I wish for the youngest is to find a stimulating and caring laboratory where they can grow professionally and personally. My advice? Find a question that you are passionate about and never lose sight of it. Question yourself, change your point of view, accept failure and contradiction but also trust yourself. Finally, share your research with your colleagues, friends and family: the greatest ideas rarely pop up from a single brain!"
Astrocyte Calcium Signaling Shifts the Polarity of Presynaptic Plasticity, Neuroscience - June 23
Mathieu Letellier, Yukiko Goda
Astrocytes have been increasingly acknowledged to play active roles in regulating synaptic transmission and plasticity. Through a variety of metabotropic and ionotropic receptors expressed on their surface, astrocytes detect extracellular neurotransmitters, and in turn, release gliotransmitters to modify synaptic strength, while they can also alter neuronal membrane excitability by modulating extracellular ionic milieu. Given the seemingly large repertoire of synaptic modulation, when, where and how astrocytes interact with synapses remain to be fully understood. Previously, we have identified a role for astrocyte NMDA receptor and L-VGCC signaling in heterosynaptic presynaptic plasticity and promoting the heterogeneity of presynaptic strengths at hippocampal synapses. Here, we have sought to further clarify the mode by which astrocytes regulate presynaptic plasticity by exploiting a reduced culture system to globally evoke NMDA receptor-dependent presynaptic plasticity. Recording from a postsynaptic neuron intracellularly loaded with BAPTA, briefly bath applying NMDA and glycine induces a stable decrease in the rate of spontaneous glutamate release, which requires the presence of astrocytes and the activation of A1 adenosine receptors. Upon preventing astrocyte calcium signaling or blocking L-type VGCCs, NMDA + glycine application triggers an increase, rather than a decrease, in the rate of spontaneous glutamate release, thereby shifting the presynaptic plasticity to promote an increase in strength. Our findings point to a crucial and surprising role of astrocytes in controlling the polarity of NMDA receptor and adenosine-dependent presynaptic plasticity. Such a pivotal mechanism unveils the power of astrocytes in regulating computations performed by neural circuits and is expected to profoundly impact cognitive processes.
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