Regulation of amygdalar PKA by β-arrestin-2/phosphodiesterase-4 complex is critical for fear conditioning

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 51; pp. 21918 - 21923
• Main Authors: Li, Yuting, Li, Haohong, Liu, Xing, Bao, Guobin, Tao, Yezheng, Wu, Ziyan, Xia, Peng, Wu, Chunfu, Li, Baoming, Ma, Lan
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22.12.2009; National Acad Sciences
• Subjects: Adenoviruses; Amygdala; Amygdala - enzymology; Animals; Arrestins - metabolism; Arrestins - physiology; Behavioral neuroscience; beta-Arrestin 2; beta-Arrestins; Biofeedback, Psychology; Biological Sciences; Blotting, Western; Conditioning, Operant; Cyclic AMP-Dependent Protein Kinases - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 4 - physiology; Fear; Freezing; Immunoprecipitation; Long term potentiation; Memory; Mice; Mice, Knockout; Neurons; Physiological regulation; Receptors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0906941106

β-arrestins, key regulators of receptor signaling, are highly expressed in the central nervous system, but their roles in brain physiology are largely unknown. Here we show that β-arrestin-2 is critically involved in the formation of associative fear memory and amygdalar synaptic plasticity. In response to fear conditioning, β-arrestin-2 translocates to amygdalar membrane where it interacts with PDE-4, a cAMP-degrading enzyme, to inhibit PKA activation. Arrb2⁻/⁻ mice exhibit impaired conditioned fear memory and long-term potentiation at the lateral amygdalar synapses. Moreover, expression of the β-arrestin-2 in the lateral amygdala of Arrb2⁻/⁻ mice, but not its mutant form that is incapable of binding PDE-4, restores basal PKA activity and rescues conditioned fear memory. Taken together, our data demonstrate that the feedback regulation of amygdalar PKA activation by β-arrestin-2 and PDE-4 complex is critical for the formation of conditioned fear memory.