School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA.
Sci Rep. 2020 Oct 26;10(1):18227. doi: 10.1038/s41598-020-75130-5.
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.
肉豆蔻酰化 ζ 抑制肽（ZIP）最初被开发为蛋白激酶 C/Mζ（PKCζ/PKMζ）抑制剂，已知其可导致不同形式记忆的丧失。然而，ZIP 即使在缺乏 PKMζ 的情况下也会引起记忆丧失，因此其作用机制仍难以捉摸。在这里，通过激酶组全谱筛选，我们发现 ZIP 在体外可强烈激活糖原合成酶激酶 3β（GSK-3β）。ZIP 诱导 LA 突触条件诱导增强的去敏（记忆擦除的细胞底物），并且 GSK-3β 抑制剂 6-溴靛红-3-乙酰胺（BIO-acetoxime）可预防 ZIP 诱导的去敏。一致地，BIO-acetoxime 输注抑制 GSK-3β 或 GSK-3β shRNA 在 LA 中的敲低可减弱 ZIP 诱导的学习性恐惧的破坏。此外，LA 中表达非抑制性 GSK-3β 形式可降低条件性恐惧。我们的研究结果表明，GSK-3β 激活是 ZIP 诱导记忆破坏的关键步骤。
