Involvement of a calcineurin cascade in amygdala depotentiation and quenching of fear memory.
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 of N-methyl-D-aspartate receptors and voltage-dependent calcium channels but is independent of adenosine A(1) 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.
Lin
Chia-Ho
CH
Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
Lee
Chia-Ching
CC
Gean
Po-Wu
PW
D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D004594:Electrophysiology; D005239:Fear / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008568:Memory / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D023421:Models, Animal; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley
D065095:Calcineurin Inhibitors; D011518:Proto-Oncogene Proteins; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin