Objectif This proposal describes experiments aimed at defining the multiple roles of vesicular glutamate transporters (VGLUTs) in central synapses. Classically, VGLUTs transport glutamate from the cytoplasm into synaptic vesicles. Deletion of these genes disrupts synaptic glutamate release and their expression suffices to determine neurons as glutamatergic. We recently discovered that VGLUTs control additional key parameters such as quantal size and vesicular release probability, suggesting that they are fundamental regulators of synaptic strength and synaptic plasticity. To study these novel functions, we will first address whether the number of VGLUTs per vesicle (VGLUT content) can affect the amount of stored glutamate and in addition, the probability of vesicle release. We will subsequently explore the underlying mechanisms. Second, we will test the hypothesis that different VGLUT paralogs contribute to functional differences in discrete synapse populations, as implied by our preliminary data and the distribution pattern of the two main paralogs VGLUT1 and VGLUT2 in the brain. Subsequently, we will perform structure function studies on VGLUTs in native synapses to identify the underlying molecular interactions. Finally, the little understood VGLUT3 paralog is expressed mainly in subclasses of cholinergic, dopaminergic and GABAergic neurons, but no evidence exists that demonstrates VGLUT3 s role in glutamate release. We will address whether VGLUT3 is used to co-release glutamate with other neurotransmitters, and will test whether presence of glutamate in synaptic vesicles interferes with the storage or release of other neurotransmitters. Our studies will yield important insights into how these transporters operate, and how modulation of VGLUTs affects synaptic encoding and brain function. Because of observed profound regulation of VGLUTs in schizophrenia, depression and Parkinsons disease, these findings will also contribute to diagnosis and treatment of mental illness. Champ scientifique medical and health sciencesbasic medicineneurologyparkinsonmedical and health sciencesclinical medicinepsychiatryschizophrenia Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) ERC-AG-LS5 - ERC Advanced Grant - Neurosciences and neural disorders Appel à propositions ERC-2009-AdG Voir d’autres projets de cet appel Régime de financement ERC-AG - ERC Advanced Grant Institution d’accueil CHARITE - UNIVERSITAETSMEDIZIN BERLIN Contribution de l’UE € 2 413 200,00 Adresse Chariteplatz 1 10117 Berlin Allemagne Voir sur la carte Région Berlin Berlin Berlin Type d’activité Higher or Secondary Education Establishments Contact administratif Martina Eickmann (Ms.) Chercheur principal Christian Rosenmund (Prof.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire CHARITE - UNIVERSITAETSMEDIZIN BERLIN Allemagne Contribution de l’UE € 2 413 200,00 Adresse Chariteplatz 1 10117 Berlin Voir sur la carte Région Berlin Berlin Berlin Type d’activité Higher or Secondary Education Establishments Contact administratif Martina Eickmann (Ms.) Chercheur principal Christian Rosenmund (Prof.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée