Cationic peptides erase memories by removing synaptic AMPA receptors through endophilin-mediated endocytosis.

Autor:	Stokes E; Pharmacology Graduate Program, University of Colorado Anschutz, Aurora, CO 80045, USA., Zhuang Y; Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA., Toledano M; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA 92697-4560., Vasquez J; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA 92697-4560., Azouz G; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA 92697-4560., Hui M; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA 92697-4560., Tyler I; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA 92697-4560., Shi X; Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.; Department of Chemistry, University of California, Irvine, CA 92697, USA.; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, USA 92697-4560., Aoto J; Pharmacology Graduate Program, University of Colorado Anschutz, Aurora, CO 80045, USA.; University of Colorado Anschutz, Department of Pharmacology, Aurora, CO 80045, USA., Beier KT; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA 92697-4560.; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, USA 92697-4560.; Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA 92697-4560.; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA 92697-4560.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Nov 21. Date of Electronic Publication: 2023 Nov 21.
DOI:	10.21203/rs.3.rs-3559525/v1
Abstrakt:	Administration of the Zeta Inhibitory Peptide (ZIP) interferes with memory maintenance and long-term potentiation (LTP). However, mice lacking its putative target, the protein kinase PKMζ, exhibit normal learning and memory as well as LTP, making ZIP's mechanism unclear. Here, we show that ZIP disrupts LTP by removing surface AMPA receptors through its cationic charge alone. This effect was fully blocked by drugs that block macropinocytosis and is dependent on endophilin A2 (endoA2)-mediated endocytosis. ZIP and other cationic peptides selectively removed newly inserted AMPAR nanoclusters, providing a mechanism by which these peptides erase memories without effects on basal synaptic function. Lastly, cationic peptides can be administered locally and/or systemically and can be combined with local microinjection of macropinocytosis inhibitors to modulate memories on local and brain-wide scales. Our findings have critical implications for an entire field of memory mechanisms and highlight a previously unappreciated mechanism by which memories can be lost. Competing Interests: Additional Declarations: There is NO Competing Interest.
Databáze:	MEDLINE
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