Reconsolidation Of Contextual Fear Memory Research Articles

Glucose may Contribute to Retrieval and Reconsolidation of Contextual Fear Memory Through Hippocampal Nr4a3 and Bdnf mRNA Expression and May Act Synergically with Adrenaline.

Adrenaline (Ad) and glucose released into the bloodstream during stress may strengthen contextual fear memory. However, no previous studies have detached the effects of glucose from Ad in this paradigm. Using Ad-deficient mice, we aimed to evaluate the effect of glucose on contextual fear memory when endogenous Ad is absent. Fear conditioning was performed in wild-type (WT) and Ad-deficient mice (129 × 1/SvJ) administered with glucose (30 or 10mg/kg; i.p.) or/and Ad (0.01mg/kg; i.p.) or vehicle (0.9% NaCl; i.p.). Catecholamines were quantified using HPLC-ED. Real-time qPCR was used to assess mRNA expression of hippocampal genes. WT and Ad-deficient mice display increased contextual fear memory when administered with glucose both in acquisition and context days when compared to vehicle. Also, Nr4a3 and Bdnf mRNA expression increased in glucose-administered Ad-deficient mice. Sub-effective doses of glucose plus Ad administered simultaneously to Ad-deficient mice increased contextual fear memory, contrary to independent sub-effective doses. Concluding, glucose may be an important part of the peripheral to central pathway involved in the retrieval and reconsolidation of fear contextual memories independently of Ad, possibly due to increased hippocampal Nr4a3 and Bdnf gene expression. Furthermore, Ad and glucose may act synergically to strengthen contextual fear memory.

Cellular mechanisms of contextual fear memory reconsolidation: Role of hippocampal SFKs, TrkB receptors and GluN2B-containing NMDA receptors.

Memories are stored into long-term representations through a process that depends on protein synthesis. However, a consolidated memory is not static and inflexible and can be reactivated under certain circumstances, the retrieval is able to reactivate memories and destabilize them engaging a process of restabilization known as reconsolidation. Although the molecular mechanisms that mediate fear memory reconsolidation are not entirely known, so here we investigated the molecular mechanisms in the hippocampus involved in contextual fear conditioning memory (CFC) reconsolidation in male Wistar rats. We demonstrated that the blockade of Src family kinases (SFKs), GluN2B-containing NMDA receptors and TrkB receptors (TrkBR) in the CA1 region of the hippocampus immediately after the reactivation session impaired contextual fear memory reconsolidation. These impairments were blocked by the neurotrophin BDNF and the NMDAR agonist, D-Serine. Considering that the study of the link between synaptic proteins is crucial for understanding memory processes, targeting the reconsolidation process may provide new ways of disrupting maladaptive memories, such as those seen in post-traumatic stress disorder. Here we provide new insights into the cellular mechanisms involved in contextual fear memory reconsolidation, demonstrating that SFKs, GluN2B-containing NMDAR, and TrkBR are necessary for the reconsolidation process. Our findings suggest a link between BDNF and SFKs and GluN2B-containing NMDAR as well as a link between NMDAR and SFKs and TrkBR in fear memory reconsolidation. These preliminary pharmacological findings provide new evidence of the mechanisms involved in the reconsolidation of fear memory and have the potential to contribute to the development of treatments for psychiatric disorders involving maladaptive memories.

Role of Hippocampal Wnt Signaling Pathways on Contextual Fear Memory Reconsolidation

Memories already consolidated when reactivated return to a labile state and can be modified, this process is known as reconsolidation. It is known the Wnt signaling pathways can modulate hippocampal synaptic plasticity as well as learning and memory. Yet, Wnt signaling pathways interact with NMDA (N-methyl-D-aspartate) receptors. However, whether canonical Wnt/β-catenin and non-canonical Wnt/Ca2 + signaling pathways are required in the CA1 region of hippocampus for contextual fear memory reconsolidation remains unclear. So, here we verified that the inhibition of canonical Wnt/β-catenin pathway with DKK1 (Dickkopf-1) into CA1 impaired the reconsolidation of contextual fear conditioning (CFC) memory when administered immediately and 2 h after reactivation session but not 6 h later, while the inhibition of non-canonical Wnt/Ca2+ signaling pathway with SFRP1 (Secreted frizzled-related protein-1) into CA1 immediately after reactivation session had no effect. Moreover, the impairment induced by DKK1 was blocked by the administration of the agonist of the NMDA receptors glycine site, D-Serine, immediately and 2 h after reactivation session. We found that hippocampal canonical Wnt/β-catenin is necessary to the reconsolidation of CFC memory at least two hours after reactivation, while non-canonical Wnt/Ca2+ signaling pathway is not involved in this process and, that there is a link between Wnt/β-catenin signaling pathway and NMDA receptors. In view of this, this study provides new evidence regarding the neural mechanisms underlying contextual fear memory reconsolidation and contributes to provide a new possible target for the treatment of fear related disorders.

Activation of a novel α2AAR-spinophilin-cofilin axis determines the effect of α2 adrenergic drugs on fear memory reconsolidation.

Posttraumatic stress disorder (PTSD) after the pandemic has emerged as a major neuropsychiatric component of post-acute COVID-19 syndrome, yet the current pharmacotherapy for PTSD is limited. The use of adrenergic drugs to treat PTSD has been suggested; however, it is hindered by conflicting clinical results and a lack of mechanistic understanding of drug actions. Our studies, using both genetically modified mice and human induced pluripotent stem cell-derived neurons, reveal a novel α2A adrenergic receptor (α2AAR)-spinophilin-cofilin axis in the hippocampus that is critical for regulation of contextual fear memory reconsolidation. In addition, we have found that two α2 ligands, clonidine and guanfacine, exhibit differential abilities in activating this signaling axis to disrupt fear memory reconsolidation. Stimulation of α2AAR with clonidine, but not guanfacine, promotes the interaction of the actin binding protein cofilin with the receptor and with the dendritic spine scaffolding protein spinophilin to induce cofilin activation at the synapse. Spinophilin-dependent regulation of cofilin is required for clonidine-induced disruption of contextual fear memory reconsolidation. Our results inform the interpretation of differential clinical observations of these two drugs on PTSD and suggest that clonidine could provide immediate treatment for PTSD symptoms related to the current pandemic. Furthermore, our study indicates that modulation of dendritic spine morphology may represent an effective strategy for the development of new pharmacotherapies for PTSD.

Activation of a novel α2AAR‐spinophilin‐cofilin axis determines the effect of α2 adrenergic drugs on fear memory reconsolidation

Posttraumatic stress disorder (PTSD) after the pandemic has emerged as a major neuropsychiatric component of the post‐acute COVID‐19 syndrome, yet the current pharmacotherapy for PTSD is limited. The use of adrenergic drugs to treat PTSD has been suggested, yet hindered by conflicting clinical results and a lack of mechanistic understanding of drug actions. Our studies using both genetically modified mice and human induced pluripotent stem cell‐derived neurons reveals a novel α2A adrenergic receptor (α2AAR)‐spinophilin‐cofilin axis in the hippocampus that is critical for regulation of contextual fear memory reconsolidation. We have further found that two a2 ligands, clonidine and guanfacine, exhibit differential abilities in activating this signaling axis to disrupt fear memory reconsolidation. Stimulation of a2AAR with clonidine, but not guanfacine, promotes the interaction of cofilin, an actin binding protein, with the dendritic spine scaffolding protein spinophilin to induce cofilin activation at the synapse. Spinophilin‐dependent regulation of cofilin is required for clonidine‐induced disruption of contextual fear memory reconsolidation. Our results inform the interpretation of differential clinical observations of these two drugs on PTSD, and suggest that clonidine could provide immediate treatment for PTSD symptoms related to the current pandemic. Furthermore, our study indicates modulation of dendritic spine morphology may represent an effective strategy for development of new pharmacotherapies for PTSD.

Effects of hippocampal IP3R inhibition on contextual fear memory consolidation, retrieval, reconsolidation and extinction

Intracellular calcium stores (ICS) play a dynamic role in neuronal calcium (Ca2+) homeostasis both by buffering Ca2+ excess in the cytoplasm or providing an additional source of Ca2+ when concentration increase is needed. However, in spite of the large body of evidence showing Ca2+ as an essential second messenger in many signaling cascades underlying synaptic plasticity, the direct involvement of the intracellular Ca2+-release channels (ICRCs) in memory processing has been highly overlooked. Here we investigated the role of the ICRC inositol 1,4,5-trisphosphate receptor (IP3R) activity during different memory phases using pharmacological inhibition in the dorsal hippocampus during contextual fear conditioning. We first found that post-training administration of the IP3R antagonist 2-aminoethyl diphenylborinate (2-APB) impaired memory consolidation in a dose and time-dependent manner. Inhibiting IP3Rs also disrupted memory retrieval. Contextual fear memory reconsolidation or extinction, however, were not sensitive to IP3R blockade. Taken together, our results indicate that hippocampal IP3Rs play an important role in contextual fear memory consolidation and retrieval.

Neural mechanism underlying regulation of emotional behavior via δ-opioid receptors

After the retrieval, consolidated fear memory undergoes reconsolidation to maintain the memory when it still necessary to remember, otherwise extinction to reduce fear response. In pathophysiology of fear-related disorders, such as PTSD and phobia, heightened/persistent fear memory has been well established. Therefore, the development of a method by which facilitates extinction or suppresses reconsolidation seems useful for the treatment of the aforementioned diseases. In this context, we show here that the activation of δ-opioid receptor (DOP) facilitates extinction and disrupts reconsolidation of contextual fear memory in mice. In addition, DOPs in the amygdala and infralimbic subregion of the medial prefrontal cortex (IL) are participate in facilitation of fear extinction. Along with the behavioral changes, excitatory synaptic transmission in the IL, a brain region positively stimulates the extinction, is enhanced by DOP activation. These results suggest that DOPs can be a target molecule for a desirable therapeutic agent for fear-related disorders.

Activation of CB1 pathway in the perirhinal cortex is necessary but not sufficient for destabilization of contextual fear memory in rats

According to the reconsolidation theory, memories can be modified through the destabilization-reconsolidation process. The rodent perirhinal cortex (PER; Brodmann areas 35 and 36) critically participates in the process of fear conditioning. Previous studies showed that some of the parahippocampal regions are critical for contextual fear memory reconsolidation. In our research, through a three-day paradigm of CFC, we showed that protein synthesis in PER of rats is required for memory reconsolidation, and activation of CB1 pathway is necessary but not sufficient in inducing memory destabilization. This result underlines parahippocampal regions in destabilization and reconsolidation process of fear memory besides amygdala and hippocampus.

Tumor necrosis factor α negatively regulates the retrieval and reconsolidation of hippocampus-dependent memory

Neural inflammation is associated with cognitive decline, especially learning and memory. Tumor necrosis factor α (TNFα) is a major cytokine generated during neuroinflammation. Previous studies indicated that TNFα impairs hippocampus-dependent memory including contextual fear and spatial memories. However, it is unknown which memory processes are impaired by TNFα. Here, we show that TNFα blocked the retrieval and reconsolidation of contextual fear and spatial memories. Micro-infusion of TNFα into the dorsal hippocampus at 6–18 h before retrieval impaired the retrieval of contextual fear memory, although micro-infusion before contextual fear conditioning had no effect on memory formation. Interestingly, hippocampal TNFα micro-infusion before memory retrieval decreased freezing responses, even at 24 h after retrieval, suggesting that TNFα impairs the reconsolidation of contextual fear memory. Similarly, hippocampal TNFα micro-infusion impaired the retrieval and reconsolidation of spatial memory in the Morris water maze. Consistent with these observations, hippocampal TNFα micro-infusion before retrieval blocked the induction of c-fos expression in the hippocampus, which is a marker of neural activation, in response to the retrieval of contextual fear memory. Collectively, our findings indicate that TNFα negatively regulates the retrieval and reconsolidation of hippocampus-dependent memory.

The Retrotransposition of L1 is Involved in the Reconsolidation of Contextual Fear Memory in Mice.

The long interspersed element-1 (L1) participates in memory formation, and DNA methylation patterns of L1 may suggest resilience or vulnerability factors for Post-Traumatic Stress Disorder (PTSD), of which the principal manifestation is a pathological exacerbation of fear memory. However, the unique roles of L1 in the reconsolidation of fear memory remain poorly understood. The study aimed to investigate the role of L1 in the reconsolidation of context-dependent fear memory. Mice underwent fear conditioning and fear recall in the observation chambers. Fear memory was assessed by calculating the percentage of time spent freezing in 5 min. The medial prefrontal cortex (mPFC) and hippocampus were removed for further analysis. Open Reading Frame 1 (ORF1) mRNA and ORF2 mRNA of L1 were analyzed by real-time quantitative polymerase chain reaction. After reactivation of fear memory, lamivudine was administered and its effects on fear memory reconsolidation were observed. ORF1 and ORF2 mRNA expressions in the mPFC and hippocampus after recent (24 h) and remote (14 days) fear memory recall exhibited augmentation via different temporal and spatial patterns. Reconsolidation of fear memory was markedly inhibited in mice treated with lamivudine, which could block L1. DNA methyltransferase mRNA expression declined following lamivudine treatment in remote fear memory recall. The retrotransposition of L1 participated in the reconsolidation of fear memory after reactivation of fear memory, and with lamivudine treatment, spontaneous recovery decreased with time after recent and remote fear memory recall, providing clues for understanding the roles of L1 in fear memory.

Function and mechanisms of memory destabilization and reconsolidation after retrieval.

Memory retrieval is not a passive process. When a memory is retrieved, the retrieved memory is destabilized, similar to short-term memory just after learning, and requires memory reconsolidation to re-stabilize the memory. Recent studies characterizing destabilization and reconsolidation showed that a retrieved memory is not always destabilized and that there are boundary conditions that determine the induction of destabilization and reconsolidation according to certain parameters, such as the duration of retrieval and the memory strength and age. Moreover, the reconsolidation of contextual fear memory is not independent of memory extinction; rather, these memory processes interact with each other. There is an increasing number of findings suggesting that destabilization following retrieval facilitates the modification, weakening, or strengthening of the original memory, and the resultant updated memory is stabilized through reconsolidation. Reconsolidation could be targeted therapeutically to improve emotional disorders such as post-traumatic stress disorder and phobia. Thus, this review summarizes recent findings to understand the mechanisms and function of reconsolidation.

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

SummaryTargeting memory reconsolidation is an effective intervention for treating posttraumatic stress disorder (PTSD). Disrupting unconditioned stimulus (US)-retrieval-induced fear memory reconsolidation has become an effective therapeutic approach to attenuate fear memory, but the underlying molecular mechanisms remain unknown. Here, we report that US-retrieval-dependent increase in phosphatidylinositol 4-kinase IIα (Pi4KIIα) promotes early endosomal trafficking of AMPA receptors, leading to the enhancement of synaptic efficacy in basolateral amygdala (BLA) neurons. The inhibition of Pi4KIIα by an inhibitor or short hairpin RNA impaired contextual fear memory reconsolidation. This disruptive effect persisted for at least 2 weeks, which was restored by Pi4KIIα overexpression with TAT-Pi4KIIα. Furthermore, the blockade of early endosomal trafficking following US retrieval reduced synaptosomal membrane GluA1 levels and decreased subsequent fear expression. These data demonstrate that Pi4KIIα in the BLA is crucial for US-retrieval-induced fear memory reconsolidation, the inhibition of which might be an effective therapeutic strategy for treating PTSD.

Inhibition of steroid receptor coactivator-1 in the hippocampus impairs the consolidation and reconsolidation of contextual fear memory in mice

AimsSteroid receptor coactivator-1 (SRC-1) is a key coactivator for the efficient transcriptional activity of steroids in the regulation of hippocampal functions. However, the effect of SRC-1 on hippocampal memory processes remains unknown. Our aim was to investigate the roles of hippocampal SRC-1 in the consolidation and reconsolidation of contextual fear memory in mice. Main methodsContextual fear conditioning paradigm was constructed in adult male C57BL/6 mice to examine the fear learning and memory processes. Adeno-associated virus (AAV) vector-mediated RNA interference (RNAi) was infused into hippocampus to block hippocampal SRC-1 level. Immunofluorescent staining was used to detect the efficiency of transfection. High plus maze and open field test were used to determine anxiety and locomotor activity. Western blot analyses were used to detect the expression of SRC-1 and synaptic proteins in the hippocampus. Key findingsWe first showed that the expression of SRC-1 was regulated by fear conditioning training in a time-dependent manner, and knockdown of SRC-1 impaired contextual fear memory consolidation without affecting innate anxiety or locomotor activity. In addition, hippocampal SRC-1 was also regulated by the retrieval of contextual fear memory, and downregulation of SRC-1 disrupted fear memory reconsolidation. Moreover, knockdown of SRC-1 reversed the increased GluR1 and PSD-95 levels induced by contextual fear memory retrieval. SignificanceOur data indicate that hippocampal SRC-1 is required for the consolidation and reconsolidation of contextual fear memory, and SRC-1 may be a potential therapeutic target for mental disorders that are involved in hippocampal memory dysfunction.

The lateral neocortex is critical for contextual fear memory reconsolidation

Memories are a product of the concerted activity of many brain areas. Deregulation of consolidation and reprocessing of mnemonic traces that encode fearful experiences might result in fear-related psychopathologies. Here, we assessed how pre-established memories change with experience, particularly the labilization/reconsolidation of memory, using the whole-brain analysis technique of positron emission tomography in male mice. We found differences in glucose consumption in the lateral neocortex, hippocampus and amygdala in mice that underwent labilization/reconsolidation processes compared to animals that did not reactivate a fear memory. We used chemogenetics to obtain insight into the role of cortical areas in these phases of memory and found that the lateral neocortex is necessary for fear memory reconsolidation. Inhibition of lateral neocortex during reconsolidation altered glucose consumption levels in the amygdala. Using an optogenetic/neuronal recording-based strategy we observed that the lateral neocortex is functionally connected with the amygdala, which, along with retrograde labeling using fluorophore-conjugated cholera toxin subunit B, support a monosynaptic connection between these areas and poses this connection as a hot-spot in the circuits involved in reactivation of fear memories.

Oxytocin receptor antagonist atosiban impairs consolidation, but not reconsolidation of contextual fear memory in rats

There is increasing evidence that oxytocin is involved in learning and memory process. This study investigated the effects of blockade of oxytocin receptors using the selective oxytocin receptor antagonist atosiban (ATO) on contextual fear memory consolidation and reconsolidation in male rats. Post-training injections of different doses of ATO (1, 10, 100 or 1000 µg/kg) impaired the 48 h retention performance in a dose-dependent manner. The same doses of ATO following memory reactivation did not impair subsequent expression of contextual fear memories which formed under low or high shock intensities and tested 24 h or one week following memory reactivation. Also, no effect was found when ATO was administrated in the absence of memory reactivation. Our finding is the first report that indicates endogenous oxytocin released during training play an important role in the consolidation, but not reconsolidation of contextual fear memory in rats.

Post-reexposure administration of riluzole attenuates the reconsolidation of conditioned fear memory in rats

Recently, we demonstrated that riluzole, which has been shown to block the glutamatergic system, facilitates fear extinction in rats. Here, we undertook experiments on contextual fear conditioning to clarify the actions of riluzole on the reconsolidation of fear memory in rats. We used the fast-acting benzodiazepine midazolam as a reconsolidation-inhibiting control drug. We demonstrated that riluzole (3 mg/kg) and midazolam (1 mg/kg) impaired the reconsolidation of contextual fear memory. Results from spontaneous recovery experiments also suggested that riluzole attenuated reconsolidation. Indeed, conditioned fear did not recover spontaneously 4 weeks after a short (3 min) reexposure and riluzole administration, whereas it recovered after a long (10 min) reexposure. Using western blotting, we demonstrated that a short reexposure increased the phosphorylation of cyclic adenosine monophosphate response element binding protein significantly in the dorsal part of hippocampus, but not in the medial prefrontal cortex. Interestingly, this phosphorylation was attenuated by riluzole with short reexposure. In addition, bilateral microinjection of riluzole (2 μM/0.2 μl/side) directly into the dorsal hippocampus clearly attenuated the reconsolidation. These findings suggested that the attenuating effect of riluzole on the reconsolidation of fear memory involves, at least in part, the dorsal part of the hippocampus. In conclusion, we demonstrated that riluzole attenuates the reconsolidation of fear memory in rats.

Hippocampal calpain is required for the consolidation and reconsolidation but not extinction of contextual fear memory

Memory consolidation, reconsolidation, and extinction have been shown to share similar molecular signatures, including new gene expression. Calpain is a Ca2+-dependent protease that exerts its effects through the proteolytic cleavage of target proteins. Neuron-specific conditional deletions of calpain 1 and 2 impair long-term potentiation in the hippocampus and spatial learning. Moreover, recent studies have suggested distinct roles of calpain 1 and 2 in synaptic plasticity. However, the role of hippocampal calpain in memory processes, especially memory consolidation, reconsolidation, and extinction, is still unclear. In the current study, we demonstrated the critical roles of hippocampal calpain in the consolidation, reconsolidation, and extinction of contextual fear memory in mice. We examined the effects of pharmacological inhibition of calpain in the hippocampus on these memory processes, using the N-Acetyl-Leu-Leu-norleucinal (ALLN; calpain 1 and 2 inhibitor). Microinfusion of ALLN into the dorsal hippocampus impaired long-term memory (24 h memory) without affecting short-term memory (2 h memory). Similarly, this pharmacological blockade of calpain in the dorsal hippocampus also disrupted reactivated memory but did not affect memory extinction. Importantly, the systemic administration of ALLN inhibited the induction of c-fos in the hippocampus, which is observed when memory is consolidated. Our observations showed that hippocampal calpain is required for the consolidation and reconsolidation of contextual fear memory. Further, the results suggested that calpain contributes to the regulation of new gene expression that is necessary for these memory processes as a regulator of Ca2+-signal transduction pathway.

IL-1β reduces GluA1 phosphorylation and its surface expression during memory reconsolidation and α-melanocyte-stimulating hormone can modulate these effects

Pro-inflammatory cytokines can affect cognitive processes such as learning and memory. Particularly, interleukin-1β (IL-1β) influences hippocampus-dependent memories. We previously reported that administration of IL-1β in dorsal hippocampus impaired contextual fear memory reconsolidation. This effect was reversed by the melanocortin alpha-melanocyte-stimulating hormone (α-MSH). Our results also demonstrated that IL-1β produced a significant decrease in glutamate release from dorsal hippocampus synaptosomes after reactivation of the fear memory. Therefore, we investigated whether IL-1β administration can affect GluA1 AMPA subunit phosphorylation, surface expression, and total expression during reconsolidation of a contextual fear memory. Also, we studied the modulatory effect of α-MSH. We found that IL-1β reduced phosphorylation of this subunit at Serine 831 and Serine 845 60 min after contextual fear memory reactivation. The intrahippocampal administration of IL-1β after memory reactivation also induced a decrease in surface expression and total expression of GluA1. α-MSH prevented the effect of IL-1β on GluA1 phosphorylation in Serine 845, but not in Serine 831. Moreover, treatment with α-MSH also prevented the effect of the cytokine on GluA1 surface and total expression after memory reactivation. Our results demonstrated that IL-1β regulates phosphorylation of GluA1 and may thus play an important role in modulation of AMPAR function and synaptic plasticity in the brain. These findings further illustrate the importance of IL-1β in cognition processes dependent on the hippocampus, and also reinforced the fact that α-MSH can reverse IL-1β effects on memory reconsolidation.

Activation of nociceptin/orphanin FQ receptors inhibits contextual fear memory reconsolidation

Several neuropeptidergic systems act as modulators of cognitive performances. Among them, nociceptin, an opioid-like peptide also known as orphanin FQ (N/OFQ), has recently gained attention. Stimulation of its receptor, the N/OFQ opioid receptor (NOP), which is expressed in brain regions involved in emotion, memory and stress response, has inhibitory effects on the acquisition and/or consolidation of spatial and emotional memory in rodents. Recently, N/OFQ was also proposed to be linked to the pathogenesis of Post-Traumatic Stress Disorder in humans. However, until now the effect of the activation of the N/OFQ-NOP system on already consolidated memory, such as during retrieval and reconsolidation phases, has never been explored. In the present study, we investigated the consequences of systemic injection of NOP agonists or i.c.v. injection of the N/OFQ peptide on the retrieval and the reconsolidation of contextual fear memory in mice. We demonstrate that the activation of the N/OFQ system impairs the reconsolidation of context-dependent but not cue-dependent aversive memories. We also show that this amnestic effect is associated with decreased c-Fos expression in the hippocampus and amygdala. Our data thus provide the first evidence that the NOP receptor could be targeted during the reconsolidation process to weaken maladaptive memories. The N/OFQ-NOP system might constitute in the future an interesting pharmacological target for interfering with so-called “pathological memories”, in particular those involving maladaptive contextual memories.

Altered AMPA receptor expression plays an important role in inducing bidirectional synaptic plasticity during contextual fear memory reconsolidation

Retrieval of a memory appears to render it unstable until the memory is once again re-stabilized or reconsolidated. Although the occurrence and consequences of reconsolidation have received much attention in recent years, the specific mechanisms that underlie the process of reconsolidation have not been fully described. Here, we present the first electrophysiological model of the synaptic plasticity changes underlying the different stages of reconsolidation of a conditioned fear memory. In this model, retrieval of a fear memory results in immediate but transient alterations in synaptic plasticity, mediated by modified expression of the glutamate receptor subunits GluA1 and GluA2 in the hippocampus of rodents. Retrieval of a memory results in an immediate impairment in LTP, which is enhanced 6h following memory retrieval. Conversely, memory retrieval results in an immediate enhancement of LTD, which decreases with time. These changes in plasticity are accompanied by decreased expression of GluA2 receptor subunits. Recovery of LTP and LTD correlates with progressive overexpression of GluA2 receptor subunits. The contribution of the GluA2 receptor was confirmed by interfering with receptor expression at the postsynaptic sites. Blocking GluA2 endocytosis restored LTP and attenuated LTD during the initial portion of the reconsolidation period. These findings suggest that altered GluA2 receptor expression is one of the mechanisms that controls different forms of synaptic plasticity during reconsolidation.