TOWARDS A COMPREHENSIVE ANALYSIS OF EXTRACELLULAR SCAFFOLDING AT THE SYNAPSE

Informations projet

C.NAPSE

N° de convention de subvention: 695295

DOI

10.3030/695295

Projet clôturé

Date de signature de la CE 23 Mai 2016

Date de début 1 Octobre 2016

Date de fin 30 Septembre 2022

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 2 492 750,00

Contribution de l’UE

€ 2 492 750,00

Coordonné par

UNIVERSITE LYON 1 CLAUDE BERNARD
France

Periodic Reporting for period 4 - C.NAPSE (TOWARDS A COMPREHENSIVE ANALYSIS OF EXTRACELLULAR SCAFFOLDING AT THE SYNAPSE)

Période du rapport: 2021-04-01 au 2022-09-30

Résumé du contexte et des objectifs généraux du projet

Chemical synapses are the specialized structures supporting communication between neurons in the brain and between neurons and muscles at neuromuscular junctions. They represent the elementary structures processing information transfer within neuronal networks and they rely on a precise molecular organization that was selected early during evolution.
The human brain might contain up to a million of billion synapses, which represents an ultimate challenge for precise characterization of these structures at the molecular scale. To reduce complexity, the current project uses the nematode C. elegans, a simple model organism that contains less than ten thousand synapses. Yet, C. elegans synapses are very similar to human synapses at the molecular level. This project takes advantage of powerful genetic strategies in combination with cutting-edge in vivo imaging and electrophysiology tools to identify new molecules and new mechanisms involved in synaptic formation and function.
The goal of this project has been to increase our fundamental knowledge of the synapse and to shed light on the physiopathology of several neuropsychiatric illnesses in which synaptic defects are at the core of the disease.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

All along this project, our team conducted several genetic screens based on the visualization of synaptic proteins in living worms and identified several new genes required for the formation and stability of chemical synapses. We identified novel synaptic proteins that are critical to recruit neurotransmitter receptors at synapses and to maintain synaptic function. We uncovered specific roles of the extracellular environment of the neurons on the stability of the synapses and we analyzed how genetic pathways controlling aging impact the integrity of the neuromuscular system. Finally, we identified unusual biophysical properties of the acetylcholine receptors at the C. elegans neuromuscular junctions that are targeted by drugs used to treat parasitic infections.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The nematode C. elegans provides a unique means of identifying critical components of synaptic organization using powerful and unbiased genetics. It has allowed the identification of novel genes required for neuro-neuronal communication. Some of these genes are associated with neuropsychiatric diseases and the basic knowledge obtained in C. elegans will provide hypotheses for a better understanding of disease pathophysiology and should ultimately contribute to the development of therapeutics.

In addition, the nematode C. elegans could represent a powerful system for the characterization of genetic variations identified by genome sequencing of patients suffering from neuropsychiatric diseases and whose biological significance is extremely difficult to establish in the absence of functional tests.

A 1 mm-long adult C. elegans expressing fluorescent proteins at neuromuscular synapses