Cationic peptides cause memory loss through endophilin-mediated endocytosis

• 成果类型: Article
• 署名作者: Stokes, Eric G.; Vasquez, Jose J.; Azouz, Ghalia; Nguyen, Megan; Tierno, Alexa; Zhuang, Yinyin; Galinato, Vivienne Mae; Hui, May; Toledano, Michael; Tyler, Isabella; Shi, Xiaoyu; Hunt, Robert F.; Aoto, Jason; Beier, Kevin T.
• 署名单位: University of Colorado System; University of Colorado Anschutz Medical Campus; University of California System; University of California Irvine; University of California System; University of California Irvine; University of California System; University of California Irvine; University of California System; University of California Irvine; University of California System; University of California Irvine; University of California System; University of California Irvine; University of Colorado System; University of Colorado Anschutz Medical Campus; University of California System; University of California Irvine; University of California System; University of California Irvine
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3553
• DOI: 10.1038/s41586-024-08413-w
• 发表日期: 2025-02-13
• 关键词: kinase-m-zeta; long-term depression; synaptic-transmission; cellular uptake; pkm-zeta; protein; expression; mechanism; ltp; INFORMATION

摘要

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 PKM zeta, exhibit normal learning and memory as well as LTP2,3, 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 on local and brain-wide scales, and these mechanisms can be leveraged to prevent memory loss in a model of traumatic brain injury. Our findings uncover a previously unknown synaptic mechanism by which memories are maintained or lost.