NF-κB transcription factor role in consolidation and reconsolidation of persistent memories

Abstract

Transcriptional regulation is an important molecular process required for long-term neural plasticity and long-term memory (LTM) formation. Thus, one main interest in molecular neuroscience in the last decades has been the identification of transcription factors that are involved in memory processes. Among them, the nuclear factor κB (NF-κB) family of transcription factors has gained interest due to a significant body of evidence that supports a key role of these proteins in synaptic plasticity and memory. In recent years, the interest was particularly reinforced because NF-κB was characterized as an important regulator of synaptogenesis. This function may be explained by its participation in synapse to nucleus communication, as well as a possible local role at the synapse. This review provides an overview of experimental work obtained in the last years, showing the essential role of this transcription factor in memory processes in different learning tasks in mammals. We focus the review on the consolidation and reconsolidation memory phases as well as on the regulation of immediate-early and late genes by epigenetic mechanisms that determine enduring forms of memories.

Keywords: NF-κB; consolidation; memory; reconsolidation; transcription factors.

Figure 1

Schematic representation of Hippocampal NF-κB involvement in different phases of memory for different memory tasks. (A–C) Inhibitory Avoidance (IA) and Fear Conditioning (FC). (A) Both in IA and in FC, training (TR) induces an increase in hippocampal NF-κB activity 45 min after TR. Administration of NF-κB inhibitory drugs—κB decoy or sulfasalazine (SSZ)—in hippocampus disrupts long-term memory (LTM) consolidation. (B) When hippocampal synaptosmal preparations were analyzed, a membrane association of NF-κB was observed 5 min post TR in IA paradigm, postulating that synaptic NF-κB not only acts as a retrograde messenger but also has a localized function as well. (C) Memory reactivation induces an increase in hippocampal NF-κB activity 15 min after re-exposure to the TR context (Re-exp), both in IA and FC. Hippocampal κB decoy or SSZ administration also impairs LTM reconsolidation in both tasks. (D–E) Novel Object Recognition (NOR). (D) Training in a NOR paradigm elicits an increment in hippocampal NF-κB activity both at 45 min and 1 h after TR. Moreover, NOR training induces an increment in hippocampal Zif268 protein, which is prevented by κB decoy administration. Both κB decoy and Zif268 antisense oligodeoxinucleotide (ODN) administration in hippocampus impair long-term recognition memory. (E) Strong TR elicits a persistent form of NOR memory which involves an increment in histone (H3) acetylation 1 h after TR, that is not observed after weaker trainings. This H3 acetylation is dependent on NF-κB activity, as κB decoy administration prevents it. In particular, CamkIIδ gene was found to be acetylated in its promoter at an NF-κB consensus sequence, which was concomitantly reversed by NF-κB inhibition. CamkIIδ mRNA levels were found to be augmented 3 h post TR. Hippocampal κB decoy administration impaired memory persistence.