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.

We thank C. Cimper and K. Marin for helpful histological assistance, M. Pontoglio for help in genome analysis, S. Tajbakhsh and C. Agulhon for kind gifts of reagents, E. Perret for help with the LSM510 software, and P.-M. Lledo and S. Tajbakhsh for critical reading of the manuscript.

This work is supported in part by grants from the INSERM and Ligue Nationale contre le Cancer (équipe labelisée) to A.I., European Community to A.I. and C.K., Volkswagen-Foundation to C.K. and M.K., Heisenberg-Stipend (DFG) to M.K., Max-Planck-Society to M.K. and V.S., and Institut Pasteur (PTR38) to S.M. S.M. is from the INSERM.