c-Rel, an NF-κB family transcription factor, is required for hippocampal long-term synaptic plasticity and memory formation

Abstract

Transcription is a critical component for consolidation of long-term memory. However, relatively few transcriptional mechanisms have been identified for the regulation of gene expression in memory formation. In the current study, we investigated the activity of one specific member of the NF-B transcription factor family, c-Rel, during memory consolidation. We found that contextual fear conditioning elicited a time-dependent increase in nuclear c-Rel levels in area CA1 and DG of hippocampus. These results suggest that c-rel is active in regulating transcription during memory consolidation. To identify the functional role of c-Rel in memory formation, we characterized c-rel −/− mice in several behavioral tasks. c-rel −/− mice displayed significant deficits in freezing behavior 24 h after training for contextual fear conditioning but showed normal freezing behavior in cued fear conditioning and in short-term contextual fear conditioning. In a novel object recognition test, wild-type littermate mice exhibited a significant preference for a novel object, but c-rel −/− mice did not. These results indicate that c-rel −/− mice have impaired hippocampus-dependent memory formation. To investigate the role of c-Rel in long-term synaptic plasticity, baseline synaptic transmission and long-term potentiation (LTP) at Schaffer collateral synapses in c-rel −/− mice was assessed. c-rel −/− slices had normal baseline synaptic transmission but exhibited significantly less LTP than did wild-type littermate slices. Together, our results demonstrate that c-Rel is necessary for long-term synaptic potentiation in vitro and hippocampus-dependent memory formation in vivo.Memory is a process through which learned information is stored, and newly formed memories are susceptible to disruption and must be stabilized for long-term storage through a process referred to as memory consolidation (McGaugh 2000). Consolidation of explicit long-term memory requires a series of hippocampus-dependent molecular processes, including gene transcription. The necessity for gene transcription to sustain longterm memory has been demonstrated in several animal models using transcription inhibitors (Thut and Lindell 1974;Kandel 2001). However, the identity and role of transcriptional mediators in long-term memory formation has yet to be fully addressed. So far, a relatively few transcription factors such as CREB, C/EBP, c-fos, and Zif268/egr-1 have been implicated in the consolidation of long-term memory (Yin et al. 1995;Jones et al. 2001;Chen et al. 2003;Fleischmann et al. 2003). Therefore in a previous study, we identified a list of candidate transcription factors that are potentially involved in the process of long-term memory consolidation using expression array profiling and a bioinformatics approach (Levenson et al. 2004a). Through these studies, the c-Rel transcription factor was identified as the most probable candidate for contributing to memory consolidation from among this novel list of transcription factors, because its DNA-binding motif is highly ...

Histone H1 Poly[ADP]-Ribosylation Regulates the Chromatin Alterations Required for Learning Consolidation

“…In Aplysia, PARP-1 activation is required for the transcription of ribosomal RNAs and ribosomal proteins (Hernández et al, 2009). Conversely, NF-Band CREB-dependent gene expression is required for learning and memory stabilization in mammals (Barco et al, 2002;Levenson et al, 2004b;Vecsey et al, 2007;Ahn et al, 2008;Fontán-Lozano et al, 2009) (for review, see Alberini, 2009). Our gene expression analysis in the hippocampus after OR training demonstrated the increase in NF-B and CREB gene targets and, in both cases, training-induced NF-B-and CREB-dependent gene expression required of PARP-1 activation.…”

“…PARP-1 regulates learning-induced gene expression by removing histone H1 from the promoters of cAMP response element-binding protein and nuclear factor-B target genes Histone H1 binds to nucleosome core particles near the entry/exit sites of linker DNA, influencing chromatin structure and gene regulation (Fan et al, 2005). It has been shown that learning consolidation requires the coordinated activation of the nuclear factor-B (NF-B) and cAMP response element-binding protein (CREB) transcription factors (Bozon et al, 2003;Ahn et al, 2008). The OR training session induced a twofold to fourfold increase in the expression of the NF-B target genes inducible nitric oxide synthase (i-nos) and tumor necrosis factor-␣ (tnf-␣), and in the CREB target genes c-fos, c-jun, and egr-1 in the hippocampus with respect to the untrained mice (for i-nos: 3.3 Ϯ 0.42-fold induction, t (8) ϭ 5.46, p Ͻ 0.001; for tnf-␣: 2.51 Ϯ 0.17-fold induction, t (8) ϭ 5.37, p ϭ 0.001; for c-fos: 2.41 Ϯ 0.45-fold induction, t (16) ϭ 2.6, p ϭ 0.018; for c-jun: 4.09 Ϯ 0.53-fold induction, t (16) ϭ 3.68, p Ͻ 0.001; and for egr-1: 4.78 Ϯ 0.38-fold induction, t (10) ϭ 4.78, p Ͻ 0.001) (Fig.…”

Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior

“…Downstream of IkK, many target genes of the NFkB transcriptional complex contribute significantly to synaptic plasticity, such as NCAM, BDNF, opioid receptors, glutamate receptors, and neuregulin (Bunting et al, 2007;Chen et al, 2006;Frensing et al, 2008;Richter et al, 2002;Saha et al, 2006). Indeed, c-Rel, a member of the NFkB transcriptional complex, is required for long-term potentiation in the hippocampus (Ahn et al, 2008). Thus, IkK is capable of integrating many extracellular signals to alter gene expression and cause long-lasting changes in neuronal function and ultimately behavior.…”

Opposing Action of Nuclear Factor κB and Polo-like Kinases Determines a Homeostatic End Point for Excitatory Synaptic Adaptation

“…The nuclear factor B (NF-B) family of transcription factors has been shown to be required for memory formation and recall in a variety of learning paradigms in both invertebrate and mammalian systems (Freudenthal and Romano, 2000;Meffert et al, 2003;Kaltschmidt et al, 2006;O'Riordan et al, 2006;Ahn et al, 2008). Previous work indicates that neuronal NF-B promotes excitatory synaptic function in the mammalian CNS, which could underlie its role in learning and memory.…”

“…Polo-like kinases (Plks) are a family of cell cycle-associated serine/threonine kinases that are co-opted in the brain to function in stabilizing changes in synaptic strength during homeostatic responses to prolonged activity. Plk2 and Plk3 family members are activity inducible and targeted to dendritic spines (Kauselmann et al, 1999;Pak and Sheng, 2003), where they promote synapse dismantling and downregulate neuronal activity (Pak and Sheng, 2003;Seeburg and Sheng, 2008;Seeburg et al, 2008) through phosphorylating proteins, including the postsynaptic spineassociated Rap GTPase-activating protein (SPAR; Pak and Sheng, 2003). Phosphorylation of SPAR leads to its degradation, which enhances overall Rap relative to opposing Ras activity, and promotes actin reorganization and dendritic spine loss, AMPAR internalization, and a depression of synaptic strength Zhu et al, 2002Zhu et al, , 2005Pak and Sheng, 2003;.…”