Role of GSK3b in fear memory

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.

Explanations

• There is a peptide developed, that inhibits protein kinase C/Mζ (PKMζ).
• This peptide is “the myristoylated zeta inhibitory peptide” or ZIP.
• Administration of ZIP leads to a loss of different forms of memories
• It was found that the loss of memories is not dependent on PKMζ.
• ZIP activates GSK3b robustly.
• Therefore, activation of GSK3b leads to a loss of memories.
• GSK-3β is required for ZIP-induced memory disruption of conditioned fear.

My overall conclusion: memory formation may require GSK3b inhibition, and fear extinction may require GSK3b activation.

This should have significant implication in “stuck” OCD - when the signal “action is complete” doesn’t form a memory due to overactive GSK3b.

This also should have implications in aversive types of OCD - when a new memory “this is safe” doesn’t form properly (overactive GSK3b) and the old memory “this is dangerous” is not erased (underactive GSK3b).