Deciphering the molecular nature of presynaptic exocytic organelles distinct from synaptic vesicles – NonSVexo

Neuronal communication at the brain requires a careful orchestration of complex trafficking events at presynaptic sites that translate electrical signals into chemical information through action potential-driven synaptic vesicle exocytosis and neurotransmitter release. However, growing information from our consortium and other groups indicates that undefined alternative organelles distinct from synaptic vesicles are capable of sensing presynaptic firing and undergo activity-driven exocytosis. Such exocytic organelles present several characteristics that are clearly distinct from synaptic vesicles: they use alternative SNARE proteins, are tetanus toxin insensitive, do not contain neurotransmitter transporters but trans-synaptic proteins, present higher internal pH and their Ca2+-driven exocytosis is poorly coupled and stochastically delayed. While we and others have identified some cargos located specifically to this undefined organelle, its molecular composition and biogenesis remain poorly understood and thus their function at the presynapse remains obscure and debated.

Here we propose a consortium that leverages the experience in synapse physiology of Jaime de Juan-Sanz, group leader at the Paris Brain Institute (ICM, France), together with the experience in the use of proteomics for studying cellular signaling of Gunnar Dittmar, group leader at the Luxembourg Institute of Health (LIH, Luxembourg). Combining proximity-labelling technologies. cutting-edge proteomics and quantitative validation both at pre- and post-synaptic sites, we will define the molecular composition of these organelles at the presynapse. We will explore the functionality of synapses in which such organelles cannot undergo exocytosis by combining genetic tools and optophysiology. This synergistic multidisciplinary approach will help defining the molecular composition of undefined presynaptic exocytic organelles, enabling our understanding of their nature and function.