Early days of electron microscopy revealed "a band of electron scattering extracellular material" that fills the 20-25 nm cleft separating the plasma membranes of two neurons engaged in a typical chemical synapse in the central nervous system (CNS). Fifty years of progress in neuroscience and molecular biology have greatly improved our understanding of the composition, function and sometimes structure of individual components of this "band". It is now clear that a multitude of adhesion molecules, neurotransmitter and other cell-surface receptors, proteoglycans and secreted proteins establish a complex network of interactions spanning the synaptic cleft. Little is known, however, about the higher order organization of the cleft molecules, once incorporated in a trans-synaptic network of interactions, and virtually nothing about the functional consequences, in both normal and pathological circumstances, of such supra-molecular arrangements.
This project will combine innovative structural biology and molecular neuroscience. Focusing on a prototypical trans-synaptic complex (several options are available, please email if interested in further details) that integrates adhesive and signalling functions, you will solve crystal structures of individual components and complexes and characterize their higher order assemblies by cryo-electron tomography. Molecular level information will be integrated in a functional context (synapse formation assays) and analyzed by fluorescence and X-ray microscopy. The aim is to decipher important principles of synaptic organization and investigate the structural plasticity of trans-synaptic protein assemblies in response to neuronal activity.