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 (<i>IL</i>) 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 (<i>Cx3cr1</i>), 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.