Propranolol decreases retention of fear memory by modulating the stability of surface glutamate receptor GluA1 subunits in the lateral amygdala

Abstract

BACKGROUND AND PURPOSEPosttraumatic stress disorder (PTSD) is a mental disorder with enhanced retention of fear memory and has profound impact on quality of life for millions of people worldwide. The β-adrenoceptor antagonist propranolol has been used in preclinical and clinical studies for the treatment of PTSD, but the mechanisms underlying its potential efficacy on fear memory retention remain to be elucidated. EXPERIMENTAL APPROACHWe investigated the action of propranolol on the retention of conditioned fear memory, the surface expression of glutamate receptor GluA1 subunits of AMPA receptors and synaptic adaptation in the lateral amygdala (LA) of rats. KEY RESULTSPropranolol attenuated reactivation-induced strengthening of fear retention while reducing enhanced surface expression of GluA1 subunits and restoring the impaired long-term depression in LA. These effects of propranolol were mediated by antagonizing reactivation-induced enhancement of adrenergic signalling, which activates PKA and calcium/calmodulin-dependent protein kinase II and then regulates the trafficking of AMPA receptors via phosphorylation of GluA1 subunits at the C-terminus. Both i.p. injection and intra-amygdala infusion of propranolol attenuated reactivation-induced enhancement of fear retention. CONCLUSIONS AND IMPLICATIONSReactivation strengthens fear retention by increasing the level of noradrenaline and promotes the surface expression of GluA1 subunits and the excitatory synaptic transmission in LA. These findings uncover one mechanism underlying the efficiency of propranolol on retention of fear memories and suggest that β-adrenoceptor antagonists, which act centrally, may be more suitable for the treatment of PTSD. Abbreviations

Enhancement of striatum-dependent memory by conditioned fear is mediated by beta-adrenergic receptors in the basolateral amygdala

“…Moreover, prior evidence indicates that increasing noradrenergic activity in the BLA is sufficient to enhance memory in a task identical to the one employed in the present study (Wingard and Packard, 2008), and the present results suggests that this effect is likely mediated through β-adrenergic receptors. Prior research indicates that exposure to fear CSs increases norepinephrine release in the amygdala (Tanaka et al., 2000, Zhou et al., 2015) and this increase in amygdala norepinephrine release may be responsible for the enhancement of habit memory observed in the present study. Future studies are necessary to examine whether increasing BLA noradrenergic activity augments the enhancement of habit memory by fear CSs and whether BLA norepinephrine levels correlates with these memory enhancements.…”

“…Similarly, Cain and colleagues (2004) reported no significant differences between mice treated (i.p.) with propranolol or vehicle in the early phases of massed auditory CS extinction or across a 60-min extinction session in a conditioned context (also, see Fitzgerald et al., 2015, Zhou et al., 2015). However, it is possible that floor effects might have competed with propranolol's effects on freezing in the current study.…”

Priming of LTP in amygdala and hippocampus by prior paired pulse facilitation paradigm in mice lacking brain serotonin

“…(Hu et al, ). Additionally, it has been shown that blocking of β‐receptors by propranolol reduced surface expression of GluA1 containing AMPARs in the LA (Zhou et al, ). Consequently, a reduced supply of NA in TPH2 −/− mice might lead to a decreased phosphorylation of AMPAR GluA1 subunits followed by a reduced surface expression of GluA1 containing AMPARs, which might cause an attenuated LTP expression.…”

Pi4KIIα Regulates Unconditioned Stimulus-Retrieval-Induced Fear Memory Reconsolidation through Endosomal Trafficking of AMPA Receptors

“…Fear memory retrieval induces transient changes in AMPAR surface expression (Hong et al, 2013;Liu et al, 2014;Rao-Ruiz et al, 2011;Zhou et al, 2015). We found that US retrieval significantly increased the levels of GluA1 (one-way ANOVA; F 3, 18 = 4.27, p = 0.0192, post hoc, USR 1 h versus NoR, p = 0.0092), GluA2 (oneway ANOVA; F 3, 18 = 5.16, p = 0.0095, post hoc, USR 1 h versus NoR, p = 0.005), and PSD95 (one-way ANOVA; F 3, 16 = 4.899, p = 0.0133, post hoc, USR 1 h versus NoR, p = 0.0217) in the synaptosomal membrane fraction of the BLA 1 h after US retrieval ( Figures 1D and 1E).…”