Arc mediates intercellular synaptic plasticity via IRSp53-dependent extracellular vesicle biogenesis.

Current models of learning and memory have focused on cell-autonomous regulation of synaptic strength; however, intercellular signaling between cells in the brain is important for normal cognition. The immediate early gene Arc is a repurposed retrotransposon critical for long-term forms of synaptic plasticity and memory. Arc protein forms virus-like capsids released in extracellular vesicles (EVs) that mediate intercellular signaling of unknown function. Here, we find that long-term potentiation stimuli induce the biogenesis of Arc EVs by recruiting the I-BAR protein IRSp53, which facilitates Arc capsid assembly, trafficking, and release from actin-rich filopodial structures in dendrites. Arc EVs transfer Arc protein and mRNA to neighboring dendrites, where translation of transferred Arc mRNA induces a loss of surface AMPA-type glutamate receptors. These results show that Arc EVs mediate an intercellular form of synaptic plasticity that may be critical for memory consolidation and reveals a new neuronal EV biogenesis pathway.