IQGAP1/ERK regulates fear memory formation via histone posttranslational modifications induced by HDAC2

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.