TOWARDS A COMPREHENSIVE ANALYSIS OF EXTRACELLULAR SCAFFOLDING AT THE SYNAPSE

Project Information

C.NAPSE

Grant agreement ID: 695295

DOI

10.3030/695295

Project closed

EC signature date 23 May 2016

Start date 1 October 2016

End date 30 September 2022

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 492 750,00

EU contribution

€ 2 492 750,00

Coordinated by

UNIVERSITE LYON 1 CLAUDE BERNARD
France

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

Reporting period: 2021-04-01 to 2022-09-30

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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