Extinction training in conjunction with a partial agonist of the glycine site on the NMDA receptor erases memory trace.
Much evidence indicates that extinction training does not erase memory traces but instead forms inhibitory learning that prevents the expression of original memory. Fear conditioning induces long-term potentiation and drives synaptic insertion of AMPA receptors into the amygdala. Here we show that extinction training applied 1 h after training reversed the conditioning-induced increase in surface glutamate receptor subunit 1 (GluR1) in parallel with the inhibition of startle potentiation. However, if applied 24 h after training, extinction training reduced startle potentiation without influencing the GluR1 increase. We infused D-cycloserine (DCS), a partial agonist of the glycine site on the NMDA receptor, bilaterally into the amygdala 30 min before extinction training. This augmented the extinction training-elicited reduction in startle and reversed the conditioning-induced increase in GluR1. Delivery of five sets of tetanic stimulation (TS) to the external capsule produced a robust enhancement of synaptic responses in the lateral amygdala neurons that persisted for >2 h. Low-frequency stimulation applied 1 h after TS had no long-lasting effect on synaptic responses. The same treatments, however, induced depotentiation in the presence of DCS and reversed TS-induced increase in surface GluR1. Together, this study has two important findings: (1) whether a memory trace remains intact or is erased depends on the interval between conditioning and extinction training and (2) DCS facilitates the reversal of memory trace. DCS-induced augmentation of extinction and reversal of GluR1 surface expression are likely mediated by DCS-facilitated endocytosis of AMPA receptors.
Mao
Sheng-Chun
SC
Institute of Basic Medical Sciences and Department of Pharmacology, Center for Gene Regulation and Signal Transduction Research, National Cheng-Kung University, Tainan 701, Taiwan.
Hsiao
Ya-Hsin
YH
Gean
Po-Wu
PW
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D003213:Conditioning, Psychological; D003523:Cycloserine / Q000494:pharmacology*; D004597:Electroshock; D005108:Extinction, Psychological; D005998:Glycine / Q000378:metabolism*; D066298:In Vitro Techniques; D008027:Light; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism*; D013237:Stereoisomerism; D013997:Time Factors
D003523:Cycloserine; D005998:Glycine; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate