Structural diversity of Arc oligomers within the excitatory synapse

The Activity-Regulated Cytoskeleton-Associated protein (Arc) is pivotal in mediating synaptic plasticity responses in neuronal cells. In vitro studies suggest its ability to form high- and low-order oligomers, which are involved in neuronal trafficking. Despite its important functions, no direct observation of Arc oligomers in cells has been presented due to its highly regulated spatiotemporal expression, the small size of the structures, the lack of appropriate labelling strategies and the background associated to free diffusing cytosolic proteins. Here, we apply super resolution microscopy to observe Arc oligomeric states in cellular environment with focus on the excitatory synapse. In cells, we provide the first evidence of Arc high-order oligomers; we uncovered intermolecular interactions of Arc, its tendency to form liquid condensates and interaction with lipid bilayers. Arc high-order oligomers affect AMPA receptor surface levels. Together, our observations suggest a model by which Arc oligomerization mediates plasma membrane negative curvature favoring AMPA receptors endocytosis.