Epigenetic mechanisms of learning and memory are particularly interesting topics in neuroscience that have recently been investigated. As shown in our previous study, IQGAP1, a scaffolding protein of MAPK, is involved in fear memory through interactions with GluN2A-containing NMDA receptors and the ERK1/2 cascade. However, researchers have not determined whether histone posttranslational modifications are regulated by the IQGAP1/ERK signaling pathway. We performed in vivo studies using IQGAP1-/- and IQGAP1+/+ mice to provide insights into the specific functions of IQGAP1 in memory processes and the precise mechanisms underlying its regulatory effects. IQGAP1-/- mice exhibited impaired fear memory, decreased levels of phosphorylated ERK1/2 and histone H3S10, decreased acetylation of H3K14, and decreased c-Fos expression in the hippocampus compared to IQGAP1+/+ mice after fear conditioning. HDAC2 was significantly enriched at the c-fos gene promoter in IQGAP1-/- mice. Correspondingly, the disruption of the epigenetic regulation induced by ERK1/2 signaling through an intra-hippocampal injection of the MEK antagonist U0126 or GluN2A-selective pharmacological antagonist NVP-AAM077 blocked context-dependent memory formation, while no changes were observed after treatment with the GluN2B-selective antagonist Ro25-6981. The administration of SAHA, a non-specific HDAC inhibitor, or knock-down of HDAC2 with shHDAC2-AAV in the dorsal hippocampus significantly rescued the impaired fear memory formation, H3S10 phosphorylation, H3K14 acetylation, and c-Fos expression in IQGAP1-/- mice. Thus, we postulated that the IQGAP1/ERK-dependent mechanism regulating histone posttranslational modifications via HDAC2 potentially underlies memory formation.

中文翻译：

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IQGAP1 / ERK通过HDAC2诱导的组蛋白翻译后修饰来调节恐惧记忆的形成。

学习和记忆的表观遗传机制是神经科学中特别有趣的主题，最近已经对其进行了研究。如我们先前的研究所示，MAPK的一种支架蛋白IQGAP1通过与含GluN2A的NMDA受体和ERK1 / 2级联的相互作用而参与恐惧记忆。但是，研究人员尚未确定组蛋白的翻译后修饰是否受IQGAP1 / ERK信号通路的调节。我们使用IQGAP1-/-和IQGAP1 + / +小鼠进行了体内研究，以深入了解IQGAP1在记忆过程中的特定功能以及其调控作用的确切机制。IQGAP1-/-小鼠表现出恐惧记忆受损，磷酸化ERK1 / 2和组蛋白H3S10降低，H3K14乙酰化降低，与恐惧调节后的IQGAP1 + / +小鼠相比，海马中c-Fos表达降低。HDAC2在IQGAP1-/-小鼠的c-fos基因启动子处显着富集。相应地，通过海马内注射MEK拮抗剂U0126或GluN2A选择性药理拮抗剂NVP-AAM077进行海马内注射，ERK1 / 2信号转导的表观遗传调控被破坏，从而阻断了上下文相关的记忆形成，而经海马内酯治疗后未观察到变化。 GluN2B-选择性拮抗剂Ro25-6981。给予SAHA（一种非特异性HDAC抑制剂）或在海马背侧用shHDAC2-AAV敲除HDAC2可以显着挽救IQGAP1-/-中恐惧记忆形成，H3S10磷酸化，H3K14乙酰化和c-Fos表达的受损。老鼠。从而，