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Updated: Jun 14, 2026
Trace Fear Conditioning in Mice
Published on: March 20, 2014
GSK-3β activation is required for ZIP-induced disruption of learned fear
Sukwoon Song1, Jihye Kim1, Kyungjoon Park2
1School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
Abstract:
The myristoylated zeta inhibitory peptide (ZIP), which was originally developed as a protein kinase C/Mζ (PKCζ/PKMζ) inhibitor, is known to produce the loss of different forms of memories. However, ZIP induces memory loss even in the absence of PKMζ, and its mechanism of action, therefore, remains elusive. Here, through a kinome-wide screen, we found that glycogen synthase kinase 3 beta (GSK-3β) was robustly activated by ZIP in vitro. ZIP induced depotentiation (a cellular substrate of memory erasure) of conditioning-induced potentiation at LA synapses, and the ZIP-induced depotentiation was prevented by a GSK-3β inhibitor, 6-bromoindirubin-3-acetoxime (BIO-acetoxime). Consistently, GSK-3β inhibition by BIO-acetoxime infusion or GSK-3β knockdown by GSK-3β shRNA in the LA attenuated ZIP-induced disruption of learned fear. Furthermore, conditioned fear was decreased by expression of a non-inhibitable form of GSK-3β in the LA. Our findings suggest that GSK-3β activation is a critical step for ZIP-induced disruption of memory.
Insights
The myristoylated zeta inhibitory peptide (ZIP) triggers memory loss by activating glycogen synthase kinase 3 beta (GSK-3β). Inhibiting GSK-3β prevents this memory disruption, revealing a new mechanism for memory erasure.
Area of Science:
- Neuroscience
- Molecular Biology
- Memory Research
Background:
- The myristoylated zeta inhibitory peptide (ZIP) is known to cause memory loss.
- ZIP's mechanism is unclear as it affects memory even without its presumed target, protein kinase Mζ (PKMζ).
Purpose of the Study:
- To elucidate the mechanism by which ZIP induces memory loss.
- To identify the molecular targets of ZIP involved in memory erasure.
Main Methods:
- A kinome-wide screen was employed to identify ZIP-activated kinases.
- In vitro and in vivo experiments using GSK-3β inhibitors (BIO-acetoxime) and knockdown (shRNA) were performed.
- Synaptic plasticity (depotentiation) and learned fear responses were assessed.
Main Results:
- Glycogen synthase kinase 3 beta (GSK-3β) was found to be activated by ZIP.
- ZIP-induced depotentiation of synaptic potentiation was blocked by a GSK-3β inhibitor.
- Inhibition or knockdown of GSK-3β in the lateral amygdala (LA) attenuated ZIP's disruption of learned fear.
- Expressing a non-inhibitable GSK-3β in the LA decreased conditioned fear.
Conclusions:
- GSK-3β activation is a crucial mediator of ZIP-induced memory disruption.
- This study reveals a novel role for GSK-3β in the cellular mechanisms underlying memory erasure.
