The dendritic spine, where the postsynaptic compartment of most excitatory synapses is localized, is a small protrusive structure emerging from the dendritic shaft. The molecular composition, the morphology and the compartmentalization of spines are critical for synaptic function. Moreover, spines are very plastic, they can appear and disappear in response to synaptic activity. Despite the importance of spine morphology and compartmentalization on synaptic function and plasticity, the molecular mechanisms according to which these structures are shaped and organized are not yet clear. The overarching objective of my project addresses these precise fundamental questions. I propose that β spectrins (2 and 3), two membrane bound actin filament cross-linking proteins, participate in setting spine morphology and compartmentalizing membrane proteins and that these functions involve their particular mechanical and lipid binding properties. The project is slip in three work packages and addresses these different aspects: (1) We will test the role of spectrins (2 and 3) on spine shape in baseline and during spine morphological changes. Morphological changes will be performed by physiological structural plasticity and innovative controlled spine deformation. A specific optical sensor will also allow us to assess directly spectrin tension in these different contexts. (2) We will investigate in detail β spectrins 2 and 3 nano and co-organization in dendritic spines. We will test the importance of their molecular partners including activity regulated lipids called phospholipids in their organizations and potential re-organization upon synaptic plasticity. (3) Finally, the dynamic compartmentalization of glutamate receptors is fundamental for synaptic function and several lines of evidence suggest that β spectrins could regulate their localization/stability in the spines. We will thus study the impact of β spectrins manipulation on synaptic functions, nano-organization and membrane dynamic of a major glutamate receptor, AMPA receptor. This grant will take full advantage of my PhD and my postdoctoral experiences in the exciting context of my new host laboratory, combining: innovative molecular tools, biophysics, electrophysiology and state-of-the-art imaging methods.