Involvement of a Calcineurin Cascade in Amygdala Depotentiation and Quenching of Fear Memory
- Dr. Po-Wu Gean, Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan 701. E-mail: powu{at}mail.ncku.edu.tw
Abstract
If fear memory is expressed by a long-term potentiation (LTP) of synaptic transmission in the amygdala, then reversal of LTP (depotentiation) in this area of the brain may provide an important mechanism for amelioration of anxiety and post-traumatic stress disorder. Herein, we show that low-frequency stimulation (LFS) of the external capsule elicits a depotentiation in the lateral nucleus of the amygdala. The induction of depotentiation requires activation ofN-methyl-d-aspartate receptors and voltage-dependent calcium channels but is independent of adenosine A1 and metabotropic glutamate group II receptors. Extracellular perfusion or loading cells with protein phosphatase (PP) 2B (calcineurin) inhibitors prevents depotentiation. The same stimulating protocol applied to the amygdala in vivo attenuates the expression of fear memory measured with fear-potentiated startle and reduces conditioning-elicited phosphorylation of Akt and mitogen-activated protein kinase (MAPK). This is paralleled by an increase in the activity of calcineurin. In addition, application of calcineurin inhibitor blocks LFS-induced extinction of fear memory and MAPK dephosphorylation. Taken together, this study characterizes the properties of LFS-induced depotentiation in the amygdala and suggests an involvement of calcineurin cascade in synaptic plasticity and memory storage.
Footnotes
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This study was supported by National Science Council grant NSC89-2320-B006-011 and by Academic Excellence Program of the Ministry of Education grant 89-B-FA08-1-4, Taiwan, Republic of China.
- Abbreviations:
- LTP
- long-term potentiation
- LFS
- low-frequency stimulation
- PP
- protein phosphatase
- EC
- external capsule
- NMDA
- N-methyl-d-aspartate
- VDCC
- voltage-dependent calcium channel
- LA
- lateral nucleus of amygdala
- MAPK
- mitogen-activated protein kinase
- ACSF
- artificial cerebrospinal fluid
- CS
- conditioned stimulus
- US
- unconditioned stimulus
- ERK
- extracellular signal-regulated kinase
- BLA
- basolateral amygdala
- FK-506
- tacrolimus
- TS
- tetanic stimulation
- fEPSP
- field excitatory postsynaptic potential
- d-APV
- d-2-amino-5-phosphonovaleate
- MK-801
- dizocilpine maleate
- DPCPX
- 8-cyclopentyl-1,3-dipropylxanthine
- EGLU
- 2S-α-ethylglutamic acid
- mGluR II
- metabotropic glutamate group II receptor
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- GluR1
- glutamate receptor 1
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- Received April 30, 2002.
- Accepted September 19, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
