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

Abstract

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 Ͼ2 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.

Mechanisms of fear extinction

“…As recovery effects have served as the impetus for new learning accounts of extinction, the lack of recovery in the short interval group would seem to be explained most parsimoniously in terms of erasure of conditioned fear and/or prevention of consolidation of fear memory. Perhaps consistent with this, evidence is emerging for a neurobiological difference between short and long interval extinction as well: Cain et al 64 reported that immediate extinction is not affected by the L-type voltage-gated calcium channel (L-VGCC) inhibitor nifedipine, whereas delayed extinction is impaired; and Mao et al 70 found that fear extinction initiated 1 h after fear acquisition reversed a fear conditioning-induced change in a particular glutamate receptor (the GluR1 subunit of the 2-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) receptor) within the amygdala, whereas this reversal did not occur when extinction was initiated 24 h after acquisition.…”

“…Based on our findings, we would argue that extinction may be mediated primarily by one process or the other, or by a combination of the two, depending on circumstances such as the timing of extinction training and perhaps other factors as well. A fuller account of the mechanistic differences between these processes is likely to emerge from cellular investigations (e.g., see Cain et al, 64 Mao et al 70 and Schwaerzel et al 73 ).…”

“…177 The effect of DCS appears to be mediated through MAPK and phosphatidylinositol 3 kinase (PI3K) in the BLA and requires both transcription and protein synthesis. 173 Finally, DCS causes a reversal of an acquisition-induced GluR1 expression increase within the BLA and facilitates the induction of synaptic depotentiation in amygdala slices, 70 which, together with the resistance of DCS-facilitated extinction to reinstatement, 175 may indicate that DCS induces erasure of fear memory.…”

Caloric Restriction Enhances Fear Extinction Learning in Mice

“…The ability to reassess cues of danger as safe has been associated with lower subjective experiences of anxiety, and inefficient fear extinction learning is present in a number of anxiety disorders (Graham and Milad, 2011). Because fear extinction learning is an active learning process that requires neural plasticity (Kaplan and Moore, 2011;Sotres-Bayon et al, 2007), genetic and pharmacologic factors that increase neural plasticity, can enhance fear extinction learning (Mao et al, 2006;Soliman et al, 2010;Sotres-Bayon et al, 2007).…”

Exposure to a fearful context during periods of memory plasticity impairs extinction via hyperactivation of frontal-amygdalar circuits

“…Many studies have demonstrated that when extinction occurs at least 24 h after initial conditioning ("delayed extinction"), crosstalk between the amygdala and prefrontal cortex mediates lasting changes in performance (Quirk and Mueller 2008;Li et al 2011). In addition, studies of the amygdala and medial prefrontal cortex have begun to show some of the substrates that underlie immediate extinction (Mao et al 2006;Clem and Huganir 2010;Kim et al 2010;Xue et al 2012). One brain region that is strongly linked with the prefrontal cortex and controls different aspects of fear expression and extinction is the intercalated cell masses (ITC) within the amygdala (Hefner et al 2008;Likhtik et al 2008;Busti et al 2011;Manko et al 2011).…”