AMPA glutamate receptors (AMPAR) play key roles in information processing by the brain as they mediate nearly all fast excitatory synaptic transmission. Their spatio-temporal organization in the post synapse with respect to presynaptic glutamate release sites is a key determinant in synaptic transmission. The activity-dependent regulation of AMPAR organization is at the heart of synaptic plasticity processes underlying learning and memory. Dysfunction of synaptic transmission - hence AMPAR organization - is likely at the origin of a number of brain diseases.
Building on discoveries made during my past ERC grant, our new ground-breaking objective is to uncover the mechanisms that link synaptic transmission with the dynamic organization of AMPAR and associated proteins. For this aim, we have assembled a team of neurobiologists, computer scientists and chemists with a track record of collaboration. We will combine physiology, cellular and molecular neurobiology with development of novel quantitative imaging and biomolecular tools to probe the molecular dynamics that regulate synaptic transmission.
Live high content 3D SuperResolution Light Imaging (SRLI) combined with electron microscopy will allow unprecedented visualization of AMPAR organization in synapses at the scale of individual subunits up to the level of intact tissue. Simultaneous SRLI and electrophysiology will elucidate the intricate relations between dynamic AMPAR organization, trafficking and synaptic transmission. Novel peptide- and small protein-based probes used as protein-protein interaction reporters and modulators will be developed to image and directly interfere with synapse organization.
We will identify new processes that are fundamental to activity dependent modifications of synaptic transmission. We will apply the above findings to understand the causes of early cognitive deficits in models of neurodegenerative disorders and open new avenues of research for innovative therapies.
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