Long-term potentiation (LTP) of excitatory synapses is widely regarded as a cellular correlate of learning and memory. Among other events, it is accompanied by an increase in the size of the postsynaptic compartment known as dendritic spines. This structural change is driven by remodelling of the actin cytoskeleton. It is widely accepted that this remodelling results from signalling cascades initiated by calcium entry through NMDA receptors. Other lines of research however highlight the necesserty for LTP maintenance of another well-known actin regulator: integrin-beta1. Integrins are extracellular matrix (ECM)-binding transmembrane receptors with no intrinsic enzymatic activity. Studies in non-neuronal cells distinguish two ways by which they transmit information across the plasma membrane: biochemical signalling, notably via the activation of tyrosin kinases, and biophysical signalling mediated by protein-protein interactions between integrins and actin. In this context, integrins are recognized as central players in the molecular assemblies responsible for cellular adhesion and motility. While integrin activation and downstream signalling have been explored in the context of LTP at the mature hippocampal synapse, little is known about the existence and potential functional impact of a physical link between the ECM and the synaptic cytoskeleton. The IntSynCity project will therefore explore this overlooked aspect of integrin regulation in the context of LTP. It will combine advanced optical imaging, molecular biology and chemical biology to i) reveal the existence of an ECM-integrin-actin link at the synapse, ii) identify the adaptor protein(s) mediating it, iii) map the nanoscale co-organisation of proteins composing these adhesion sites, relatove to each other and to other synaptic components, and iv) investigate the functional impact of such linkage on various aspects of LTP, including the AMPA receptor mediated increase in synaptic strength and the actin regulatory cascades leading to increased spine size. Taken together, this project and its technological developments will shed new light on the molecular mechanisms via which integrin-b1 regulates LTP. By filling an important knowledge gap at the crossroads of several aspects of molecular neuroscience, the project will impact both the fields of synaptic adhesion and structural plasticity. Its ambition thus perfectly aligns with the scientific topics persued in the host team, while proposing a new line of research that will enable the coordinator to achieve scientific maturity, intellectual independence and visibility among her peers.