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

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

doi:10.1038/s41467-020-17484-y

Alexey Bingor, Yael Stern-Bach + Show 3 more

Open Access

https://doi.org/10.1038/s41467-020-17484-y

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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.

Highlights

Zeta inhibitory peptide (ZIP), a PKMζ inhibitor, is widely used to interfere with the maintenance of acquired memories
Since it was well established that ZIP reduces EPSCs in CA1 hippocampal neurons together with its ability to erase established memories in PKMζ knockout mice[10,11], we hypothesized that ZIP functionally interacts with AMPA receptors (AMPARs)
PKCζ was present, we found that HEK293 cells did not express PKMζ, confirming our hypothesis that the action of ZIP is independent of PKMζ

Summary

Introduction

Zeta inhibitory peptide (ZIP), a PKMζ inhibitor, is widely used to interfere with the maintenance of acquired memories. 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. Long-term potentiation (LTP) is the leading cellular mechanism of learning and memory, and sustained activation of protein kinase M Zeta (PKMζ) is essential for its maintenance[1] This concept mostly relies on the ability of Zeta Inhibitory Peptide (ZIP), originally synthesized as a pseudosubstrate inhibitor of PKMζ2–4, to interfere with LTP and erase memory in a variety of learning tasks including spatial sensitization[5], pain sensitization[6], fear-associated memories[7], conditioned taste aversion[8] and development of locomotor sensitization in rodents[9]. Subsequent downregulation of AMPARs activity results in attenuation of cocaine-conditioned reward

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