ABA Renewal Involves Enhancements in Both GluA2-Lacking AMPA Receptor Activity and GluA1 Phosphorylation in the Lateral Amygdala

Abstract

Fear renewal, the context-specific relapse of fear following fear extinction, is a leading animal model of post-traumatic stress disorders (PTSD) and fear-related disorders. Although fear extinction can diminish fear responses, this effect is restricted to the context where the extinction is carried out, and the extinguished fear strongly relapses when assessed in the original acquisition context (ABA renewal) or in a context distinct from the conditioning and extinction contexts (ABC renewal). We have previously identified Ser831 phosphorylation of GluA1 subunit in the lateral amygdala (LA) as a key molecular mechanism for ABC renewal. However, molecular mechanisms underlying ABA renewal remain to be elucidated. Here, we found that both the excitatory synaptic efficacy and GluA2-lacking AMPAR activity at thalamic input synapses onto the LA (T-LA synapses) were enhanced upon ABA renewal. GluA2-lacking AMPAR activity was also increased during low-threshold potentiation, a potential cellular substrate of renewal, at T-LA synapses. The microinjection of 1-naphtylacetyl-spermine (NASPM), a selective blocker of GluA2-lacking AMPARs, into the LA attenuated ABA renewal, suggesting a critical role of GluA2-lacking AMPARs in ABA renewal. We also found that Ser831 phosphorylation of GluA1 in the LA was increased upon ABA renewal. We developed a short peptide mimicking the Ser831-containing C-tail region of GluA1, which can be phosphorylated upon renewal (GluA1S); thus, the phosphorylated GluA1S may compete with Ser831-phosphorylated GluA1. This GluA1S peptide blocked the low-threshold potentiation when dialyzed into a recorded neuron. The microinjection of a cell-permeable form of GluA1S peptide into the LA attenuated ABA renewal. In support of the GluA1S experiments, a GluA1D peptide (in which the serine at 831 is replaced with a phosphomimetic amino acid, aspartate) attenuated ABA renewal when microinjected into the LA. These findings suggest that enhancements in both the GluA2-lacking AMPAR activity and GluA1 phosphorylation at Ser831 are required for ABA renewal.

Regulation of Fear Extinction in the Basolateral Amygdala by Dopamine D2 Receptors Accompanied by Altered GluR1, GluR1-Ser845 and NR2B Levels

“…As previously reported, auditory fear conditioning is accompanied by enhanced synaptic plasticity at auditory input synapses in the BLA, and extinction reverses both the enhanced synaptic efficacy and the conditioning-induced enhancement of surface AMPAR expression ( Lin et al, 2009 ). Additionally, when rodents exhibit renewal, there is increased GluR2-lacking AMPA signaling in the LA ( Lee et al, 2013 ; Park et al, 2014 ). Considering these results, we speculate that lower AMPAR expression is accompanied by less freezing behavior, which is in line with our results demonstrating that the facilitated extinction caused by D2 receptors decreased the expression of AMPARs.…”

Posterior parietal cortex mediates fear renewal in a novel context

“…During fear renewal, synaptic efficacy of the thalamo-amygdala pathway increases. Some synaptic mechanisms for this increase in synaptic efficacy have been studied: the activity of GluA2-lacking the AMPA receptor is increased [14], and the phosphorylation of GluA1 at serine 831 is required to produce fear renewal [15].…”

Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

“…In the lateral amygdala (LA) injecting a peptide that mimics the GluA1 carboxy terminus membrane proximal region has a detrimental effect on fear memory acquisition (Ganea et al 2015). Phosphorylation of GluA1 S831 in the LA is important in fear renewal (Lee et al 2013;Park et al 2014), while GluA1-pS845 plays a role in the ventral striatum in spatial learning (Ferretti et al 2015). Lithium, a common treatment used for bipolar disease, also has anti-depressant effects on behaviors assayed by the tail suspension test and forced swim test in an AMPAR dependent manner (Gould et al 2008).…”