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 critical 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 signal cell-to-cell. Here, we find that long-term potentiation (LTP) stimuli induce the biogenesis of Arc EVs by recruiting the I-BAR protein IRSp53 to dendrites, which facilitates Arc capsid assembly and release. Arc EVs transfer Arc protein and mRNA to neighboring neurons, where translation of transferred Arc mRNA induces a loss of surface AMPA-type glutamate receptors. These results show that Arc EVs mediate non-cell autonomous long-term depression (LTD), revealing an intercellular form of synaptic plasticity that may be critical for memory consolidation. ### Competing Interest Statement J.D.S is a co-founder of VNV, LLC and a consultant for Aera Therapeutics, Inc.