Cpeb1 remodels cell type–specific translational program to promote fear extinction

Protein translation is crucial for fear extinction, a process vital for adaptive behavior and mental health, yet the underlying cell-specific mechanisms remain elusive. Using a Tet-On 3G genetic approach, we achieved precise temporal control over protein translation in the infralimbic medial prefrontal cortex ( IL ) during fear extinction. In addition, our results reveal that the disruption of cytoplasmic polyadenylation element binding protein 1 (Cpeb1) leads to notable alterations in cell type–specific translational programs, thereby affecting fear extinction. Specifically, Cpeb1 deficiency in neurons activates the translation of heterochromatin protein 1 binding protein 3, which enhances microRNA networks, whereas in microglia, it suppresses the translation of chemokine receptor 1 ( Cx3cr1 ), resulting in an aged-like microglial phenotype. These coordinated alterations impair spine formation and plasticity. Our study highlights the critical role of cell type–specific protein translation in fear extinction and provides an insight into therapeutic targets for disorders with extinction deficits.