Vesicular trafficking in the formation and maintenance of the neuronal and immunological synapses – NeuroImmunoSynapse

The central nervous and immune systems rely upon molecular signaling and cellular communication initiated by direct cell to cell contact. The term Synapse was coined by Sherrington from the Greek “syn” (together) and “haptein” (to clasp) to indicate neuronal cell to cell contact sites. The term immune synapse describes a variety of cell to cell junctions between cells of the immune system. Both neuronal and immunological synapses accumulate molecules present both at the plasma membrane and in secretory vesicles. By concentrating signaling mechanisms into two-dimensional microdomains, synapses raise the effective concentrations of kinases, adaptor molecules, and ion channels, thereby promoting efficient local signaling and greatly accelerating the kinetics of reaction networks. It also controls the release of soluble molecules in a confined synaptic cleft.
How synapses are formed and maintained is still largely an open question.
The structure of neuronal and immune synapses presents similarities and specificities. In both cases, the pre- and postsynaptic cells interact through a synaptic cleft and communicate through secreted effectors. Heterophilic and homophilic interactions of adhesion molecules mediate cell–cell contacts. In both synapses, the delivery of effectors is regulated in time and space and polarized delivery of soluble and transmembrane proteins plays an important role. Both synapses are sites of intense cytoskeletal dynamics and vesicular traffic.
The literature and our preliminary results suggest that the secretory pathways mediated by the vesicular SNARE proteins VAMPs 1, 2, 3 and 7, and their regulators, play a crucial role in immune and neuronal synapses formation, maintenance and function. These observations lead us to propose the present project based on KO mice and other available tools to decipher the function of these secretory pathways in neurons and immune cells.
Our working hypothesis is that vesicular trafficking is crucial for the formation, maintenance, and function of both neuronal and immune synapses. We propose to characterize the cell biology of vesicular trafficking in the context of mutations deleting VAMPs 1, 2, 3 and/or 7.
To this end, we will pursue 3 specific aims: 1) Characterize the VAMP2, 3, and 7 cargoes at the protein and lipid levels in T lymphocytes and embryonic neurons from KO mice after purification of VAMP2 and VAMP7 vesicles from embryonic neurons and VAMP3 and VAMP7 vesicles from T lymphocytes, 2) Characterize synapse formation in VAMPs 1, 2 and 7 KO and double KO neurons in primary culture, and in VAMP3 and VAMP7 KO- and double KO lymphocytes in culture and 3) Study the neuronal synapses in vivo in VAMP7 KO mice and the immunity in vivo in VAMP7 and VAMP3 and double KO mice.
One of the originality of this ambitious project relies on the complementary approaches of the two groups that have already collaborated for 3 years and are experts respectively in the formation of the neuronal and immunological synapses. The results we expect to obtain have great potential to advance our understanding of the role of vesicular traffic at neuronal and immune synapses and to enable the development of novel therapies by identifying novel targets for the central nervous and immune systems.