ABSTRACT
A long-standing hypothesis posits that a G protein-coupled signaling pathway mediates ß-adrenergic nervous system functions, including learning and memory. Here we report that memory retrieval (reactivation) induces the activation of ß1-adrenergic ß-arrestin signaling in the brain, which stimulates ERK signaling and protein synthesis, leading to postreactivation memory restabilization. ß-Arrestin2-deficient mice exhibit impaired memory reconsolidation in object recognition, Morris water maze, and cocaine-conditioned place preference paradigms. Postreactivation blockade of both brain ß-adrenergic Gs protein- and ß-arrestin-dependent pathways disrupts memory reconsolidation. Unexpectedly, selective blockade of the Gs/cAMP/PKA signaling but not the ß-arrestin/ERK signaling by the biased ß-adrenergic ligands does not inhibit reconsolidation. Moreover, the expression of ß-arrestin2 in the entorhinal cortex of ß-arrestin 2-deficient mice rescues ß1-adrenergic ERK signaling and reconsolidation in a G protein pathway-independent manner. We demonstrate that ß-arrestin-biased signaling regulates memory reconsolidation and reveal the potential for ß-arrestin-biased ligands in the treatment of memory-related disorders.
