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Nano-Scale Organization Dynamics and Functions of Synapses: from single molecule tracking to the physiopathology of excitatory synaptic transmission

Final Report Summary - NANO-DYN-SYN (Nano-Scale Organization Dynamics and Functions of Synapses: from single molecule tracking to the physiopathology of excitatory synaptic transmission)

Synapses are arguably the most elaborate signaling machine of cells. This complex intercellular junction is specialized for rapid (millisecond) directional signaling. In addition, synapses change in response to patterns of neural activity and these changes can endure, modifying neuronal circuitry. These competing properties of persistence and plasticity must be encoded by the precise content and arrangement of molecules that comprise the presynaptic and postsynaptic specializations.
Our objective was to uncover the internal organization and dynamics of the postsynaptic specialization at excitatory glutamatergic synapses of the mammalian brain at an unprecedented nano-scale resolution. For this aim, neurobiologists, physicists and chemists have joined forces in a team with proven track record of collaboration. We have combined cellular and molecular neurobiology approaches with development of novel optical technologies, biosensors and combined quantitative light and electron microscopic imaging. This has provided a new level of analysis to the fundamental problem of molecular information storage.
We have advanced several key steps in our understanding of glutamate receptor dynamic organization and role of this trafficking in synaptic plasticity. We have found that stargazin phosphorylation triggers the diffusional trapping and hence accumulation of the AMPAR-stargazin complex at synapses via association to PSD95. This event might be at the core of long-term potentiation (LTP) of synaptic transmission, a cellular correlate of memory.
Super resolution imaging of single receptors has allowed unprecedented quantitative imaging and tracking of protein trafficking. We have unraveled a new nanoscale organization of glutamate receptors that changes our view on fast synaptic transmission. Novel biosensors and chemical tools have been developed for the investigation of the dynamic macromolecular events underlying synaptic plasticity.
This project has allowed identifying new mechanisms that control fast synaptic transmission and its long term activity dependent modification. We have started to unravel how fast receptor diffusion controls frequency dependent synaptic transmission and how regulation of receptor trafficking participates to synaptic plasticity.
We have performed pioneering work to monitor the movements of single molecules on living neurons by labeling with organic dyes and quantum dots. This has led to the emergence of new concepts in synaptic transmission, namely that synaptic proteins are in a dynamic equilibrium and that receptor movements modulate fast synaptic transmission. Using chemical biology approaches, we have developed bioprobes to understand receptor-scaffold interactions and have identified AMPAR surface diffusion as a possible pharmacological target to treat brain diseases.