Abstract

The efficiency and accuracy of neurotransmission strongly depends on two apparently antagonist properties of synaptic membrane: the stability of its organization and its ability to adapt to plasticity events. In addition, the structural stability of synapses has to be reconciled with the notion that cell membranes are fluid. Membrane molecules are compelled to move within the membrane surface due to thermal Brownian agitation, which favors the homogeneous distribution of the molecules. As a result, neurons spend energy to stop or reduce these movements, and maintain molecules in certain locations via mechanisms that decrease this fluidity. We have approached these conceptual paradoxes by developing new technological and analytical tools that allow the monitoring of the behavior of synaptic components at the molecular level and change of the scale of analysis. We demonstrated rapid exchanges between synaptic and extra-synaptic receptors and we showed that transient stabilization of receptors at synapses occurs by interaction with partners, such as scaffold proteins. Novel super-resolution imaging methods (PALM, STORM ) gave us a precise insight on the organization of these postsynaptic structures. Thus combination of single particle tracking and super-resolution methods, open access to molecular counting and energy involved in receptor-scaffold interactions as well as on and off rate of molecular interactions. Thus beyond super-resolution methods is chemistry “in cellulo” accounting for the regulation of receptor number and consecutively that of synaptic strength. Ultimately, the dynamic regulations of receptor-scaffold and scaffold–scaffold interactions appear as a central tenet for the maintenance and plasticity-related changes of receptor numbers at synapses. These processes are likely to be deregulated in pathological situations such as in neurodegenerative diseases.