A Bioinformatics Analysis of Memory Consolidation Reveals Involvement of the Transcription Factor c-Rel

Abstract

Consolidation of long-term memory (LTM) is a complex process requiring synthesis of new mRNAs and proteins.Many studies have characterized the requirement for de novo mRNA and protein synthesis; however, few studies have comprehensively identified genes regulated during LTM consolidation. We show that consolidation of long-term contextual memory in the hippocampus triggers altered expression of numerous genes encompassing many aspects of neuronal function. Like contextual memory formation, this altered gene expression required NMDA receptor activation and was specific for situations in which the animal formed an association between a physical context and a sensory stimulus. Using a bioinformatics approach, we found that regulatory elements for several transcription factors are over-represented in the upstream region of genes regulated during consolidation of LTM. Using a knock-out mouse, we found that c-rel, one of the transcription factors identified in our bioinformatics study, is necessary for hippocampus-dependent long-term memory formation.

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…Using a bioinformatic approach, c-Rel binding sites were found to be enriched in the upstream region of genes regulated during consolidation of LTM. This involvement of c-Rel in hippocampus-dependent LTM formation was confirmed in gene expression studies using c-rel À/À mice (Levenson et al, 2004).…”

Roles for NF-κB in nerve cell survival, plasticity, and disease

“…[2][3][4][5] However, other complexes are present in neurons and their subunit composition may vary depending upon factors such as the developmental state of the neurons and their location within the nervous system. 6,7 The canonical mechanism of NF-kB activation involves phosphorylation of the inhibitory IkB subunit by the IkB kinase complex (IKK); 8 phosphorylation targets IkB for ubiquitination and subsequent proteasomal degradation, thereby releasing the active NF-kB factor dimer ( Figure 1). NF-kB then translocates to the nucleus and binds to kB sites in promoters of target genes.…”

“…28 In contrast, c-Rel-deficient mice were reported to show decreased exploratory activity and no change in anxiety-related behavior on the open-field test. 7 While these contrasts are intriguing, it is probably too early to know whether any or all of these possible differences in subunit function are actual or only apparent due to the limited number of studies.…”

“…The cognate binding motif for NF-kB was significantly enriched in the regulatory regions of consolidation-associated genes from hippocampal area CA1 compared to randomly selected genes. 7 Which genes contained regulatory regions for NF-kB, out of their 38 plasticity-associated genes from hippocampal area CA1, as well as the functionality of the identified kB-sites, remain to be detailed.…”

Current insights into the regulation of programmed cell death by NF-κB

“…Mice lacking c-Rel exhibit defects in contextual fear memory (Levenson et al, 2004). On the other hand, RelA has been implicated in facilitating spatial memory formation and synaptic plasticity (Meffert et al, 2003), although it was suggested that inactivation of RelA might not be the only contributing factor to the memory defect of RelAÀ/ÀTNF-R1À/À mice, as TNF-R1 deficiency was previously described to alter synaptic plasticity in in vitro preparations (Albensi and Mattson, 2000).…”