Identification of calcineurin as a key signal in the extinction of fear memory.
Memory extinction refers to a gradual decrease of the previously acquired response when exposed to conditional stimulus without pairing with unconditional stimulus. Here we show for the first time that fear training-induced phosphorylation of specific substrates in the rat amygdala is reduced after extinction trials and is accompanied by an increase in the protein level and enzymatic activity of calcineurin. In parallel, calcineurin inhibitors prevented extinction-induced protein dephosphorylation as well as extinction of fear memory. Thus, extinction training increased phosphatase activity likely via an expression of calcineurin. Calcineurin then created a negative-feedback loop and directly or indirectly dephosphorylated specific substrates, which, in their phosphorylated state, were required for memory consolidation. Accordingly, in our experimental condition, extinction could be ascribed at least in part to a weakening of the original signaling.
Lin
Chih-Hung
CH
Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan City, Taiwan 701.
Yeh
Shiu-Hwa
SH
Leu
Tzeng-Horng
TH
Chang
Wen-Chang
WC
Wang
Shan-Tair
ST
Gean
Po-Wu
PW
D000679:Amygdala / Q000378:metabolism; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D003213:Conditioning, Psychological / Q000502:physiology; D004597:Electroshock; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology; D008568:Memory / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D013216:Reflex, Startle / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D019703:Calcineurin; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt