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SynAdh

Mécanismes moléculaires et cellulaires impliqués dans la formation et la spécialisation des synapses neuronales par les molécules d’adhérence neurexines, neuroligines, et LRRTMs.

Le projet porté par Olivier Thoumine compte trois partenaires:

  • Olivier Thoumine responsable de l'équipe "Biophysique de l'adhésion et du cytosquelette"
  • Matthieu Sainlos de l'équipe "Dynamique de l'organisation et des fonctions synaptiques"- CNRS UMR 5297 - Institut Interdisciplinaire de Neurosciences - Daniel Choquet
  • Pascale Marchot de l' UMR CNRS 7257 - Architecture et Fonction des Macromolécules Biologiques - Université Aix-Marseille

Abstract

Assembly of the myriad of synapses enabling communication between neurons is a crucial process of the CNS development and dictates the generation, maintenance and functioning of neural circuitries. Moreover, the function and specificity of synapses make them the locus of expression of most neurological disorders. This project aims at better characterizing the molecular and cellular mechanisms underlying synapse formation, maturation and specification.

At the level of individual axon/dendrite contacts, synaptogenesis is a complex process initiated by recognition of specific adhesion proteins and followed by the recruitment of scaffolding molecules and functional receptor-channels. Among celladhesion molecules, the neurexins (NRXN), neuroligins (NLGN) and leucine-rich repeat transmembrane proteins (LRRTM) are implicated in synapse formation, differentiation and functional validation. In the mammalian brain, specific recognition between isoforms and splice variants of these molecules dictate the formation of, mainly : i) excitatory synapses relying on presynaptic glutamate release in front of AMPARs and NMDARs, which are stabilized at the postsynapse by NLGN1, LRRTM2, and PDZ domain-containing scaffolding molecules such as PSD-95; ii) inhibitory synapses relying on presynaptic GABA release, which activates GABARs stabilized by NLGN2 and scaffolding molecules such as gephyrin. Pathological mutations in the NRXN and NLGN genes are related to autism, X-linked mental retardation and schizophrenia, supporting the need of studying how adhesion molecules modulate synapse formation and functioning. However, the mechanisms by which these molecules, besides maintaining together axonal and dendritic membranes, dynamically assemble functional pre- and postsynaptic elements are still unclear.

The study of synaptogenesis is hindered by the limited spatial resolution of conventional microscopy and the lack of selective molecules able to promote or perturb synapse formation. This project is aimed at overcoming these limitations by developing i) new strategies for protein labeling with small fluorescent probes combined with super-resolution imaging, ii) new peptidic ligands designed after the 3D structures of the extra- and intracellular domains of the adhesion proteins and to be used as interaction modulators. This project should lead to a better understanding of the role of adhesion molecules in the assembly of synapses and to the rational design of new therapeutic agents alleviating neurodevelopmental disorders.

To address this multi-disciplinary and ambitious project, we built a consortium of three teams with complementary expertise. The first two teams, of O. Thoumine and M. Sainlos from the same institute (IINS, Bordeaux), have been collaborating for several years and interact on a day-to-day basis. They will bring their respective expertise in the biology of synaptic adhesion molecules, cell culture systems, high-resolution imaging and electrophysiology, and in the design and production of peptides mimicking the interaction of adhesion molecules to their extra- and intracellular partners. The third team associates P. Marchot, a biochemist and pharmacologist, and Yves Bourne, a structural biologist, who have strong collaborative records and now work in the same lab (AFMB, Marseille). They will add their complementary expertise in documenting the structure-function relationships of various ligand-receptor and protein-protein complexes and their functional implications.

Our program involves three main collaborative tasks:
Task 1. Structure-function analysis of the extracellular NRXN/LRRTM complexes and design of peptidic effectors of the NRXN interactions with NLGN and LRRTM
Task 2. Intracellular interactions of the NRXNs, NLGNs and LRTTMs with scaffolding molecules, characterization of novel peptidic effectors, and high-resolution microscopy of the complexes
Task 3: Signaling and other functions mediated by the NRXNs, NLGNs and LRRTMs