Regulation of amygdalar PKA by beta-arrestin-2/phosphodiesterase-4 complex is critical for fear conditioning.
Beta-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 beta-arrestin-2 is critically involved in the formation of associative fear memory and amygdalar synaptic plasticity. In response to fear conditioning, beta-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 beta-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 beta-arrestin-2 and PDE-4 complex is critical for the formation of conditioned fear memory.
Li
Yuting
Y
The State Key Laboratory of Medical Neurobiology, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
Li
Haohong
H
Liu
Xing
X
Bao
Guobin
G
Tao
Yezheng
Y
Wu
Ziyan
Z
Xia
Peng
P
Wu
Chunfu
C
Li
Baoming
B
Ma
Lan
L
D000679:Amygdala / Q000201:enzymology*; D000818:Animals; D019390:Arrestins / Q000378:metabolism / Q000502:physiology*; D001676:Biofeedback, Psychology; D015153:Blotting, Western; D003216:Conditioning, Operant; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism / Q000502:physiology*; D005239:Fear; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605258:Arrb2 protein, mouse; D019390:Arrestins; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4