Volume 13 Issue 5 - April 9, 2010 PDF
Involvement of ubiquitin-proteasome system in the D-cycloserine-induced augmentation of fear memory extinction
Sheng-Chun Mao, Hui-Ching Lin and Po-Wu Gean*
Professor of Department of Pharmacology, College of Medicine, National Cheng Kung University
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Consistent with previous reports, we found that DCS infused bilaterally into the amygdala before extinction training augmented reduction of startle potentiation. Unexpectedly, conditioning-induced increase in GluR1 was reversed by DCS in combination with extinction training. By measuring GluR1 internalization using cell-surface biotinylation techniques, the purpose of this study was to elucidate the possible mechanism of DCS and to determine whether the ubiquitin-mediated proteasome activity was required for this process.

DCS selectively increased NMDA receptor-mediated synaptic response without affecting AMPA receptor-mediated synaptic response. Low-frequency stimulation (LFS) when applied in the presence of DCS induced GluR1 and GluR2 internalization in the amygdala slices. Proteasome inhibitors block DCS facilitation of LFS-induced depotentiation and a reduction in surface levels of GluR1 and GluR2. Furthermore, DCS in combination with LFS reduced cellular levels of PSD-95 and synapse-associated protein 97 (SAP97), which were also blocked by proteasome inhibitors. In the in vivo experiments, DCS-induced reduction of fear potentiated startle and reversal of conditioning-induced increase in surface expression of GluR1 were blocked by proteasome inhibitors. DCS-treated rats fail to exhibit reinstatement after US-alone presentations. These results suggest that DCS facilitates receptor internalization in the presence of extinction training, resulting in augmented reduction of startle potentiation.

In summary, augmentation of extinction is a potential approach to the treatment of maladaptive memory disorders such as post-traumatic stress phobias. Extinction training involves repeated non-reinforced re-exposure to the CS, resulting in a new memory being formed (CS_no US), and so the fear response to the CS is subsequently attenuated. The demonstration of DCS-induced GluR1 and GluR2 internalization suggests that facilitation of extinction by DCS not only could result from the enhancement of new extinction memory but also could be attributed, at least in part, to an erasure of the original fear memory.
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