The ubiquitin–proteasome system as a critical regulator of synaptic plasticity and long-term memory formation

Jarome, Timothy J.; Helmstetter, Fred J.

doi:10.1016/j.nlm.2013.03.009

Cited by 127 publications

(100 citation statements)

References 118 publications

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“…Although the molecular mechanisms underlying the reconsolidation process have only begun to be elucidated, a number of recent studies have focused on changes in ubiquitin-proteasome activity and AMPA receptor subunit exchange as potential regulators of memory reconsolidation (reviewed in, Jarome and Helmstetter, 2013a). For example, inhibition of proteasome activity prevents the initiation of the reconsolidation process Jarome et al, 2011) and can prevent reconsolidation-dependent memory strengthening (Lee, 2008).…”

Section: Discussionmentioning

confidence: 99%

Contextual Information Drives the Reconsolidation-Dependent Updating of Retrieved Fear Memories

Jarome

Ferrara

Kwapis

et al. 2015

Neuropsychopharmacol

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Stored memories enter a temporary state of vulnerability following retrieval known as 'reconsolidation', a process that can allow memories to be modified to incorporate new information. Although reconsolidation has become an attractive target for treatment of memories related to traumatic past experiences, we still do not know what new information triggers the updating of retrieved memories. Here, we used biochemical markers of synaptic plasticity in combination with a novel behavioral procedure to determine what was learned during memory reconsolidation under normal retrieval conditions. We eliminated new information during retrieval by manipulating animals' training experience and measured changes in proteasome activity and GluR2 expression in the amygdala, two established markers of fear memory lability and reconsolidation. We found that eliminating new contextual information during the retrieval of memories for predictable and unpredictable fear associations prevented changes in proteasome activity and glutamate receptor expression in the amygdala, indicating that this new information drives the reconsolidation of both predictable and unpredictable fear associations on retrieval. Consistent with this, eliminating new contextual information prior to retrieval prevented the memory-impairing effects of protein synthesis inhibitors following retrieval. These results indicate that under normal conditions, reconsolidation updates memories by incorporating new contextual information into the memory trace. Collectively, these results suggest that controlling contextual information present during retrieval may be a useful strategy for improving reconsolidation-based treatments of traumatic memories associated with anxiety disorders such as post-traumatic stress disorder.

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Section: Discussionmentioning

confidence: 99%

Contextual Information Drives the Reconsolidation-Dependent Updating of Retrieved Fear Memories

Jarome

Ferrara

Kwapis

et al. 2015

Neuropsychopharmacol

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“…Similarly, it is unlikely that we would see reduced freezing if our manipulation disrupted reconsolidation. Blocking NMDA receptors prevents memory destabilization (Ben Mamou et al 2006), effectively blocking the initiation of reconsolidation (Johansen et al 2011;Jarome and Helmstetter 2013). Therefore, if intra-IL APV primarily affected reconsolidation, higher freezing would be anticipated, as the original fear memory would persist.…”

Section: Discussionmentioning

confidence: 99%

The role of the medial prefrontal cortex in trace fear extinction

2014

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The extinction of delay fear conditioning relies on a neural circuit that has received much attention and is relatively well defined. Whether this established circuit also supports the extinction of more complex associations, however, is unclear. Trace fear conditioning is a better model of complex relational learning, yet the circuit that supports extinction of this memory has received very little attention. Recent research has indicated that trace fear extinction requires a different neural circuit than delay extinction; trace extinction requires the participation of the retrosplenial cortex, but not the amygdala, as noted in a previous study. Here, we tested the roles of the prelimbic and infralimbic regions of the medial prefrontal cortex in trace and delay fear extinction by blocking NMDA receptors during extinction learning. We found that the prelimbic cortex is necessary for trace, but not for delay fear extinction, whereas the infralimbic cortex is involved in both types of extinction. These results are consistent with the idea that trace fear associations require plasticity in multiple cortical areas for successful extinction. Further, the infralimbic cortex appears to play a role in extinction regardless of whether the animal was initially trained in trace or delay conditioning. Together, our results provide new information about how the neural circuits supporting trace and delay fear extinction differ.

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“…The amygdala is a critical site of plasticity for the formation of fear memories in the brain (LeDoux 2000). Consistent with this, inhibiting gene transcription, protein synthesis, and protein degradation in the amygdala impairs fear memory consolidation following behavioral training (Bailey et al 1999;Parsons et al 2006;Jarome et al 2011) leading to the theory that a coordinated regulation of changes in gene transcription in the amygdala is necessary for the formation of fear memories (Johansen et al 2011;Jarome and Helmstetter 2013). However, although some studies have suggested a role for posttranslational modification of histone mediated chromatin remodeling in the consolidation of fear memories in the amygdala (Koshibu et al 2009;Monsey et al 2011;Mahan et al 2012), it is unknown if histone lysine methylation is required for lateral amygdala (LA)-dependent fear memory consolidation.…”

mentioning

confidence: 91%

NMDA receptor- and ERK-dependent histone methylation changes in the lateral amygdala bidirectionally regulate fear memory formation

et al. 2014

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It is well established that fear memory formation requires de novo gene transcription in the amygdala. We provide evidence that epigenetic mechanisms in the form of histone lysine methylation in the lateral amygdala (LA) are regulated by NMDA receptor (NMDAR) signaling and involved in gene transcription changes necessary for fear memory consolidation. Here we found increases in histone H3 lysine 9 dimethylation (H3K9me2) levels in the LA at 1 h following auditory fear conditioning, which continued to be temporally regulated up to 25 h following behavioral training. Additionally, we demonstrate that inhibiting the H3K9me2 histone lysine methyltransferase G9a (H/KMTs-G9a) in the LA impaired fear memory, while blocking the H3K9me2 histone lysine demethylase LSD1 (H/KDM-LSD1) enhanced fear memory, suggesting that H3K9me2 in the LA can bidirectionally regulate fear memory formation. Furthermore, we show that NMDAR activity differentially regulated the recruitment of H/KMT-G9a, H/KDM-LSD1, and subsequent H3K9me2 levels at a target gene promoter. This was largely regulated by GluN2B-but not GluN2A-containing NMDARs via ERK activation. Moreover, fear memory deficits associated with NMDAR or ERK blockade were successfully rescued through pharmacologically inhibiting LSD1, suggesting that enhancements of H3K9me2 levels within the LA can rescue fear memory impairments that result from hypofunctioning NMDARs or loss of ERK signaling. Together, the present study suggests that histone lysine methylation regulation in the LA via NMDAR-ERK-dependent signaling is involved in fear memory formation.

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The ubiquitin–proteasome system as a critical regulator of synaptic plasticity and long-term memory formation

Cited by 127 publications

References 118 publications

Contextual Information Drives the Reconsolidation-Dependent Updating of Retrieved Fear Memories

Contextual Information Drives the Reconsolidation-Dependent Updating of Retrieved Fear Memories

The role of the medial prefrontal cortex in trace fear extinction

NMDA receptor- and ERK-dependent histone methylation changes in the lateral amygdala bidirectionally regulate fear memory formation

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