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The Journal of Neuroscience, August 30, 2006, 26(35):8892-8899; doi:10.1523/JNEUROSCI.0365-06.2006

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Behavioral/Systems/Cognitive
Extinction Training in Conjunction with a Partial Agonist of the Glycine Site on the NMDA Receptor Erases Memory Trace

Sheng-Chun Mao, Ya-Hsin Hsiao, and Po-Wu Gean

Institute of Basic Medical Sciences and Department of Pharmacology, Center for Gene Regulation and Signal Transduction Research, National Cheng-Kung University, Tainan 701, Taiwan

Correspondence should be addressed to Dr. Po-Wu Gean, Department of Pharmacology (Rm-82-0823), College of Medicine, National Cheng-Kung University, 1 Ta-Shieh Road, Tainan 701, Taiwan. Email: powu{at}mail.ncku.edu.tw

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.

Key words: amygdala; extinction; fear; glutamate receptor; depotentiation; learning and memory

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Received Jan. 25, 2006; revised June 20, 2006; accepted July 20, 2006.

Correspondence should be addressed to Dr. Po-Wu Gean, Department of Pharmacology (Rm-82-0823), College of Medicine, National Cheng-Kung University, 1 Ta-Shieh Road, Tainan 701, Taiwan. Email: powu{at}mail.ncku.edu.tw

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