NF-κB Regulates Spatial Memory Formation and Synaptic Plasticity through Protein Kinase A/CREB Signaling

Abstract

Synaptic activity-dependent de novo gene transcription is crucial for long-lasting neuronal plasticity and long-term memory. In a forebrain neuronal conditional NF-κB-deficient mouse model, we demonstrate here that the transcription factor NF-κB regulates spatial memory formation, synaptic transmission, and plasticity. Gene profiling experiments and analysis of regulatory regions identified the α catalytic subunit of protein kinase A (PKA), an essential memory regulator, as a new NF-κB target gene. Consequently, NF-κB inhibition led to a decrease in forskolin-induced CREB phosphorylation. Collectively, these results disclose a novel hierarchical transcriptional network involving NF-κB, PKA, and CREB that leads to concerted nuclear transduction of synaptic signals in neurons, accounting for the critical function of NF-κB in learning and memory.

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

“…In fact, a transgenic line expressing the super-repressor, IkBa-SR, predominately in interneurons, leads to a hyperexcitable state characterized by increased long-term potentiation, spatial learning, and seizures (O'Mahony et al, 2006). Perhaps not surprising, a transgenic line expressing the Tet-O inducible superrepressor under the CamKII-a promoter, shows opposite behavioral changes, namely deficits in spatial learning (Kaltschmidt et al, 2006). These behavioral deficits were accompanied by impaired long-term potentiation and reduced forskolin-induced CREB phosphorylation.…”

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

“…These researchers subsequently used this model to explore the relationship between NF-kB and synaptic activity-dependent transcription, which is crucial for long-lasting neuronal plasticity and long-term memory. NF-kB was found to regulate spatial memory formation by controlling the expression of the alpha catalytic subunit of protein kinase A, an important regulator of CREB (cAMP response element binding protein) signalling in this process (Kaltschmidt et al, 2006).…”

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

“…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). Further supporting a role for NFkB in learning and memory, neuronal ablation of NFkB by tetracycline-dependent expression of an IkBa super-repressor also gives rise to defects in spatial memory formation (Kaltschmidt et al, 2006). However, contrary to NF-kB's effects in response to stress or injury, its role in these physiological contexts seems to be independent of its effect on apoptosis, as RelAÀ/À TNF-R1-deficient mice or mice with targeted inhibition of NF-kB in the forebrain show normal CNS development and no defect in neuronal survival (Fridmacher et al, 2003;Meffert et al, 2003).…”