Cationic peptides cause memory loss through endophilin-mediated endocytosis.

ABSTRACT: The zeta inhibitory peptide (ZIP) interferes with memory maintenance and long-term potentiation (LTP)¹ when administered to mice. However, mice lacking its putative target, protein kinase PKMζ, exhibit normal learning and memory as well as LTP^2,3, making the mechanism of ZIP unclear. Here we show that ZIP disrupts LTP by removing surface AMPA receptors through its cationic charge alone. This effect requires endophilin-A2-mediated endocytosis and is fully blocked by drugs suppressing macropinocytosis. ZIP and other cationic peptides remove newly inserted AMPA receptor nanoclusters at potentiated synapses, providing a mechanism by which these peptides erase memories without altering basal synaptic function. When delivered in vivo, cationic peptides can modulate memories

SUBMITTER: Stokes EG 

PROVIDER: S-EPMC12413077 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature