Zeta Inhibitory Peptide attenuates learning and memory by inducing NO-mediated downregulation of AMPA receptors

Alexey Bingor, Tomer Haham, Claire Thornton, Yael Stern-Bach, Rami Yaka*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Zeta inhibitory peptide (ZIP), a PKMζ inhibitor, is widely used to interfere with the maintenance of acquired memories. ZIP is able to erase memory even in the absence of PKMζ, via an unknown mechanism. We found that ZIP induces redistribution of the AMPARGluA1 in HEK293 cells and primary cortical neurons, and decreases AMPAR-mediated currents in the nucleus accumbens (NAc). These effects were mimicked by free arginine or by a modified ZIP in which all but the arginine residues were replaced by alanine. Redistribution was blocked by a peptidase-resistant version of ZIP and by treatment with the nitric oxide (NO)-synthase inhibitor L-NAME. ZIP increased GluA1-S831 phosphorylation and ZIP-induced redistribution was blocked by nitrosyl-mutant GluA1-C875S or serine-mutant GluA1-S831A. Introducing the cleavable arginine-alanine peptide into the NAc attenuated expression of cocaine-conditioned reward. Together, these results suggest that ZIP may act as an arginine donor, facilitating NO-dependent downregulation of AMPARs, thereby attenuating learning and memory.

Original languageAmerican English
Article number3688
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - 1 Dec 2020

Bibliographical note

Funding Information:
We thank the late Dr. Jehoshua Katzhendler for his technical support, Dr. Avi Priel for valuable feedback on this manuscript, and Dr. Anat Ben-Yaacov for technical help at the initial stage of the study. This work was supported by the Israel Science Foundation (ISF; 1283/16 R.Y.), the National Institute for Psychobiology in Israel (NIPI), the David R. Bloom Center for Pharmacy at the Hebrew University of Jerusalem (R.Y.), the Royal Society (C.T. and R.Y.) and by an internal grant from IMRIC (Y.S.-B.).

Publisher Copyright:
© 2020, The Author(s).

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