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Identification of calcineurin as a key signal in the extinction of fear memory - PubMed

  • ️Wed Jan 01 2003

Identification of calcineurin as a key signal in the extinction of fear memory

Chih-Hung Lin et al. J Neurosci. 2003.

Abstract

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.

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Figures

Fig. 1.
Fig. 1.

Effect of extinction training on the fear-potentiated startle. A, Timeline of behavioral procedures for experiments B. B, Percentage of startle potentiation before (pre-test), during, and after three sessions of extinction training, context exposure, or light–shock (post-test). The degree of potentiation was significantly reduced only in the light-alone group. It is noted that unpaired controls did not exhibit a decrease in startle responses. *p < 0.05, **p < 0.01, and ***p < 0.001 versus pretests.

Fig. 2.
Fig. 2.

Effect of extinction training on conditioning-induced Akt phosphorylation. A, Behavioral procedure used in experiment B. B, Time course of PI-3 kinase activation in paired as opposed to those of unpaired and naive rats. Shown are the representative blots and mean ± SE ratios of P-Akt/Akt immunoreactivities from rats decapitated at 30, 60, 90, 120, 150, and 180 min (n = 6 rats in each time point) after pretests. The −10 min time point represents the level of Akt phosphorylation 24 hr after training but before test, whereas the 0 min time point is the value taken from naive rats. *p< 0.01 versus unpaired control. C, Behavioral procedure used in experiment D. D, Rats received fear training in a paired or unpaired manner and were tested 24 hr later (pretest). Shown are the representative blots and mean ± SE percentage of P-Akt immunoreactivities from unpaired (lane 1) and paired (lane 2) rats decapitated at 60 min after pretest. Ten minutes after pretest, paired rats were given light-alone trials (lane 3) or exposed to the context (lane 4), and the amygdala was removed for biochemical assay. The degree of Akt phosphorylation was significantly reduced in the light-alone group. Bilateral infusion of FK-506 (10 μg dissolved in 1.6 μl of DMSO, 0.8 μl per side) before light-alone trials blocked dephosphorylation (lane 5). *p < 0.01 versus pretest.

Fig. 3.
Fig. 3.

Extinction training-induced reduction of fear memory is blocked by calcineurin inhibitors. Percentage of startle potentiation before (pretest) and after three sessions of extinction training in conditioned rats given intravenous administration of cyclosporin A (5 or 20 mg/kg), bilateral amygdala infusion of FK-506 (10 μg dissolved in 1.6 μl of DMSO, 0.8 μl per side), or cypermethrin (3 μg dissolved in 1.6 μl of ethanol, 0.8 μl per side) before light-alone trials. *p < 0.01 and **p < 0.001 versus pretests.

Fig. 4.
Fig. 4.

Increase in the enzymatic activity and protein expression of calcineurin after extinction training. A, Rats were assigned into three groups (naive, unpaired, and paired; 12 rats in each group), and each group was trained according to its own protocol. After training, six rats in each group were killed, and the release of Pi from LA and BLA was measured. Next, the remaining six rats in each group were subjected to extinction training, and calcineurin activity was measured after training. After extinction training, the release of Pi was enhanced only in the paired rats. ***p < 0.001 versus naive or unpaired groups.B, Time course of calcineurin expression induced by light-alone trials in cytosolic fraction. Shown are representative blots and mean ± SE of calcineurin immunoreactivities from rats decapitated at various time points (n = 6 rats in each time point) after extinction training (α-actin was used as internal control). **p < 0.01 and ***p < 0.001 versus paired.

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