title: β-Arrestin-biased signaling mediates memory reconsolidation.
abstract: A long-standing hypothesis posits that a G protein-coupled signaling pathway mediates β-adrenergic nervous system functions, including learning and memory. Here we report that memory retrieval (reactivation) induces the activation of β1-adrenergic β-arrestin signaling in the brain, which stimulates ERK signaling and protein synthesis, leading to postreactivation memory restabilization. β-Arrestin2-deficient mice exhibit impaired memory reconsolidation in object recognition, Morris water maze, and cocaine-conditioned place preference paradigms. Postreactivation blockade of both brain β-adrenergic Gs protein- and β-arrestin-dependent pathways disrupts memory reconsolidation. Unexpectedly, selective blockade of the Gs/cAMP/PKA signaling but not the β-arrestin/ERK signaling by the biased β-adrenergic ligands does not inhibit reconsolidation. Moreover, the expression of β-arrestin2 in the entorhinal cortex of β-arrestin 2-deficient mice rescues β1-adrenergic ERK signaling and reconsolidation in a G protein pathway-independent manner. We demonstrate that β-arrestin-biased signaling regulates memory reconsolidation and reveal the potential for β-arrestin-biased ligands in the treatment of memory-related disorders.
authors.affiliation: The State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and the Institutes of Brain Science, and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and the Institutes of Brain Science, and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: The State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and the Institutes of Brain Science, and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Hao Hong
authors.initials: HH
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and the Institutes of Brain Science, and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Huang
authors.affiliation: The State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and the Institutes of Brain Science, and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: You Xing
authors.initials: YX
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and the Institutes of Brain Science, and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Ye Zheng
authors.initials: YZ
authors.lastname: Tao
authors.affiliation: The State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and the Institutes of Brain Science, and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China lanma@fudan.edu.cn.
authors.forename: Lan
authors.initials: L
authors.lastname: Ma
mesh_terms: D000526:Alprenolol / Q000737:chemistry; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D001921:Brain / Q000187:drug effects; D001931:Brain Mapping / Q000379:methods; D002227:Carbazoles / Q000737:chemistry; D000077261:Carvedilol; D003042:Cocaine / Q000737:chemistry; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011412:Propanolamines / Q000737:chemistry; D011433:Propranolol / Q000737:chemistry; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605258:Arrb2 protein, mouse; D019390:Arrestins; D002227:Carbazoles; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000077261:Carvedilol; D000526:Alprenolol; D011433:Propranolol; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D003042:Cocaine
keywords: biased receptor signaling; memory reconsolidation; β-adrenergic receptor; β-arrestin2
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