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

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 PKMz, exhibit normal learning and memory as well as LTP, making ZIP’s mechanism unclear. Here, we show that ZIP disru...

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Autores principales: Beier, Kevin, Stokes, Eric, Zhuang, Yinyin, Toledano, Michael, Vasquez, Jose, Azouz, Ghalia, Hui, May, Tyler, Isabella, Shi, Xiaoyu, Aoto, Jason
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690331/
https://www.ncbi.nlm.nih.gov/pubmed/38045269
http://dx.doi.org/10.21203/rs.3.rs-3559525/v1
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author Beier, Kevin
Stokes, Eric
Zhuang, Yinyin
Toledano, Michael
Vasquez, Jose
Azouz, Ghalia
Hui, May
Tyler, Isabella
Shi, Xiaoyu
Aoto, Jason
author_facet Beier, Kevin
Stokes, Eric
Zhuang, Yinyin
Toledano, Michael
Vasquez, Jose
Azouz, Ghalia
Hui, May
Tyler, Isabella
Shi, Xiaoyu
Aoto, Jason
author_sort Beier, Kevin
collection PubMed
description 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 PKMz, 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.
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spelling pubmed-106903312023-12-02 Cationic peptides erase memories by removing synaptic AMPA receptors through endophilin-mediated endocytosis Beier, Kevin Stokes, Eric Zhuang, Yinyin Toledano, Michael Vasquez, Jose Azouz, Ghalia Hui, May Tyler, Isabella Shi, Xiaoyu Aoto, Jason Res Sq Article 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 PKMz, 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. American Journal Experts 2023-11-21 /pmc/articles/PMC10690331/ /pubmed/38045269 http://dx.doi.org/10.21203/rs.3.rs-3559525/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Beier, Kevin
Stokes, Eric
Zhuang, Yinyin
Toledano, Michael
Vasquez, Jose
Azouz, Ghalia
Hui, May
Tyler, Isabella
Shi, Xiaoyu
Aoto, Jason
Cationic peptides erase memories by removing synaptic AMPA receptors through endophilin-mediated endocytosis
title Cationic peptides erase memories by removing synaptic AMPA receptors through endophilin-mediated endocytosis
title_full Cationic peptides erase memories by removing synaptic AMPA receptors through endophilin-mediated endocytosis
title_fullStr Cationic peptides erase memories by removing synaptic AMPA receptors through endophilin-mediated endocytosis
title_full_unstemmed Cationic peptides erase memories by removing synaptic AMPA receptors through endophilin-mediated endocytosis
title_short Cationic peptides erase memories by removing synaptic AMPA receptors through endophilin-mediated endocytosis
title_sort cationic peptides erase memories by removing synaptic ampa receptors through endophilin-mediated endocytosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690331/
https://www.ncbi.nlm.nih.gov/pubmed/38045269
http://dx.doi.org/10.21203/rs.3.rs-3559525/v1
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