Molecular analysis of assembly and function of surface AMPA-receptor complexes in the mammalian brain

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Glutamate receptors of the AMPA-type (AMPARs), the central players of excitatory neurotransmission in the brain, are multi-protein complexes whose molecular appearance and functional properties are encoded by their proteome (or interactome), the ensemble of their protein building blocks. These more than 30 distinct proteins identified by our original proteomic analyses define the biogenesis of the ‘receptor-core’ in the endoplasmic reticulum, as well as the assembly of the ‘receptor periphery’ finally building the mature AMPAR complexes at synaptic and extra-synaptic sites of the plasma membrane. In fact, our recent analyses strongly suggest that the constituents of the receptor periphery are major determinants for proper operation of AMPARs in synapses, as well as their activity-dependent dynamics and adaptations that are fundamental for learning and memory formation. This proposal aims at a comprehensive molecular understanding of the surface AMPAR complexes (characterized by the ‘periphery forming’ interactome constituents), with focus on their assembly, their dynamics, their interactions with synaptic proteins and their significance for receptor-mediated neurotransmission and plasticity. For this purposes we will apply an interdisciplinary approach comprising biochemistry and proteomic analyses, electro-physiology, as well as fluorescence- and electron-microscopy.