PROJECT: JTC2009: MODDIFSYN

Surface trafficking (lateral diffusion) has recently emerged to be a key process to regulate ionotropic glutamate receptor numbers at excitatory synapses and to control fast excitatory synaptic transmission. Dysfunction of this process is likely to be at the basis of the abnormal synaptic transmission and plasticity observed in several neurodegenerative diseases. At present no tools are available to specifically modulate receptor surface trafficking in intact tissues. We selected glutamate receptors themselves and extracellular matrix proteins (ECM) as lead targets to achieve this modulation. The main objective of this project is thus to develop new chemical and optical tools to study and modulate glutamate receptor surface trafficking in synaptic transmission in different models of neurodegenerative diseases. We want to: WP1) Develop new optical tools to image receptor trafficking in brain slices and in vivo (Choquet, Tamp‚, Gundelfinger). WP2) Develop new chemical tools for site-specific labeling and photo-activatable cross-linking of glutamate receptors and ECM proteins (Tamp‚, Choquet, Gundelfinger). WP3) Develop new reporters to identify ECM modifying extracellular proteases using fluorogenic protease substrates (Gundelfinger, Kaczmarek) WP4) Use these tools to study the fundamental role and modulation of AMPA and NMDA glutamate receptor surface trafficking in normal fast synaptic transmission (Choquet, Tamp‚, Bioulac, Gundelfinger, Kaczmarek) WP5) Apply these knowledge and tools to study and correct the defects in receptor trafficking in different neurodegenerative and neurological diseases. Namely in Parkinson?s disease (Bioulac), Alzheimer?s disease (Choquet) and temporal lobe epilepsy (Kaczmarek).?