Disruption of AMPA Receptor Endocytosis Impairs the Extinction, but not Acquisition of Learned Fear

Abstract

Synaptic plasticity in the form of long-term potentiation (LTP) plays a critical role in the formation of a Pavlovian fear association. However, the role that synaptic plasticity plays in the suppression of a learned fear response remains to be clarified. Here, we assessed the role that long-term depression (LTD) plays in the acquisition, expression, and extinction of a conditioned fear response. We report that blockade of LTD with a GluR2-derived peptide (Tat-GluR2 3Y ; 1.5 mmol/kg, i.v.) that blocks regulated a-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor endocytosis during an initial extinction training session disrupted both the expression and recall of extinction learning. A similar impairment of extinction during training, but not recall, was observed when NMDA receptor-dependent LTD was inhibited through the selective blockade of NMDA NR2B receptors with Ro 25-6981. In contrast, blockade of LTD with Tat-GluR2 3Y during fear conditioning or during a fear recall test did not effect the expression or recall of either contextual or cue-induced conditioned fear. Similarly, administration of Tat-GluR2 3Y prior to an extinction recall test did not affect spontaneous recovery or rate of re-extinction in previously extinguished rats. These data demonstrate that AMPA receptor endocytosis does not mediate acquisition or expression of conditioned fear, but may play a role in the extinction of fear memories. Furthermore, these findings suggest that LTD may be a molecular mechanism that facilitates the selective modification of a learned association while leaving intact the ability to form a new memory.

Sleep deprivation affects extinction but not acquisition memory in honeybees

“…If deprivation of sleep is more related to the function of the mushroom bodies ( Joiner et al 2006) than consolidation of memory after such configural forms as extinction, then learning may be more strongly affected. Furthermore, several studies have shown that acquisition learning and extinction learning are different in many aspects (Bouton et al 1993;Myers and Davis 2002;Gottfried and Dolan 2004;Eisenhardt and Menzel 2007), and conditions have been reported that interfere with consolidation of extinction memory while sparing other forms of memory (Silvestri 2005;Fu et al 2007;Dalton et al 2008). It is thus possible that sleep deprivation affects only extinction learning, a question that needs to be addressed in further experiments.…”

Calcineurin inhibition blocks within-, but not between-session fear extinction in mice

“…targets have also been implicated in memory destabilization during reconsolidation Hong et al 2013) and in extinction (Kim et al 2007;Dalton et al 2008;Lee et al 2008), suggesting that this memory labilization system might mediate both the labilization component of reconsolidation and the within-session component of memory extinction.…”

Long-Term Neural Correlates of Reversible Fear Learning in the Lateral Amygdala

“…Fear extinction recruits the infralimbic cortex to exert inhibitory influence on the medial subnuclei of the central amygdala (CeM) via the basal amygdala (BA) and amygdala-intercalated neurons (Maren and Quirk, 2004;Haubensak et al, 2010;Pape and Pare, 2010;Amir et al, 2011). Extinction also induces depotentiation at LA input synapses (Kim et al, 2007;Dalton et al, 2008;Hong et al, 2009) and enhances local inhibition (Chhatwal et al, 2005;Lin et al, 2009), all leading to decreased fear expression. Interestingly, NMDA receptor blockers infused into the LA impair both fear conditioning and extinction, suggesting that neuronal plasticity in the LA is crucial for both events (Miserendino et al, 1990;Falls et al, 1992;Sotres-Bayon et al, 2007).…”