β-Arrestin-biased signaling mediates memory reconsolidation

A long-standing hypothesis posits that a G protein-coupled signaling pathway mediates beta-adrenergic nervous system functions, including learning and memory. Here we report that memory retrieval (reactivation) induces the activation of beta(1)-adrenergic beta-arrestin signaling in the brain, which stimulates ERK signaling and protein synthesis, leading to postreactivation memory restabilization. beta-Arrestin2-deficient mice exhibit impaired memory reconsolidation in object recognition, Morris water maze, and cocaine-conditioned place preference paradigms. Postreactivation blockade of both brain beta-adrenergic Gs protein-and beta-arrestindependent pathways disrupts memory reconsolidation. Unexpectedly, selective blockade of the Gs/cAMP/PKA signaling but not the beta-arrestin/ERK signaling by the biased beta-adrenergic ligands does not inhibit reconsolidation. Moreover, the expression of beta-arrestin2 in the entorhinal cortex of beta-arrestin 2-deficient mice rescues beta(1)-adrenergic ERK signaling and reconsolidation in a G protein pathway-independent manner. We demonstrate that beta-arrestinbiased signaling regulates memory reconsolidation and reveal the potential for beta-arrestin-biased ligands in the treatment of memoryrelated disorders.