Acquisition of Fear Extinction Requires Activation of NR2B-Containing NMDA Receptors in the Lateral Amygdala

Abstract

N-methyl-D-aspartate receptors (NMDARs) contribute to synaptic plasticity underlying learning in a variety of brain systems. Fear extinction, which involves learning to suppress the expression of previously learned fear, appears to require NMDAR activation in the amygdala. However, it is unclear whether amygdala NMDARs are required for the acquisition of extinction learning, and it is unknown whether NR2B-containing NMDARs are required in fear extinction. Here, we assessed the effects of selective NR2B blockade with ifenprodil on fear extinction learning, and found that both systemic and intra-amygdala ifenprodil treatment, given before extinction training, impaired the initial acquisition, and subsequent retrieval of fear extinction. These results confirm previous evidence showing that NMDARs in the amygdala are involved in fear extinction, and additionally show that NR2B-containing NMDARs are required. Contrary to the conclusion of previous studies, our findings demonstrate NMDARs are required for the initial acquisition, rather than only the retention, of fear extinction learning. Thus, our results support a previously not known role for NMDA-dependent plasticity in the lateral amygdala during the acquisition of fear extinction.

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

“…Sotres-Bayon et al (2007) report impairment in the acquisition of fear extinction in rats treated with the NR2B-subunit-selective NMDA receptor antagonist ifenprodil. Furthermore, this noncompetitive NMDA antagonist disrupts synaptic plasticity in the amygdala (Bauer et al, 2002).…”

“…Thus, freezing was only scored if the rat was immobile for at least 1 s (Maren, 1998). We verified the threshold output of freezing behavior with video scoring of the animals' response which was defined as the cessation of all movement with the exception of respiration-related movement and nonawake or rest body posture (Sotres-Bayon et al, 2007).…”

“…Day 4FExtinction recall test: 20 presentations of the CS only (mean ITI 180 s, range 120-240 s). Although all rats received 20 CS presentations on 'Extinction recall test' days, data analysis was restricted to the first 10 CS presentations, in accordance with previous studies of this nature (Sotres-Bayon et al, 2007). This was necessary because the majority of rats in all groups extinguished their freezing behavior early in the session and subsequently displayed 'sleeping postures' before all 20 tones were presented.…”

“…More recent studies suggest a specific role for the NR2B subunit containing NMDA receptors in the expression and recall of extinction. Sotres-Bayon et al (2007) report that the selective NMDA NR2B subunit-selective antagonist ifenprodil prevents both the expression of extinction and the recall of extinction training 24 h later. Given that these manipulations also disrupt LTP (Bauer et al, 2002), it has been proposed that impairments in fear extinction induced by NMDA receptor blockade are attributable to disruptions in LTP-like mechanisms that mediate the formation of new learning associated with extinction.…”

“…For example, long-term potentiation (LTP) is considered to be a candidate mechanism of neural plasticity that mediates the acquisition and storage of new fear memories, particularly in the lateral nuclei of the amygdala. Treatments that block LTP, such as NMDA receptor antagonists, calcium channel blockers, and protein synthesis inhibitors, disrupt the extinction of conditioned fear (Falls et al, 1992;Vianna et al, 2001;Santini et al, 2004;Sotres-Bayon et al, 2007). Conversely, drugs that promote LTP can facilitate extinction (Walker and Davis, 2002;Yang and Lu, 2005).…”