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NF-κB functions in synaptic signaling and behavior

Nature Neuroscience volume 6, pages 1072–1078 (2003)Cite this article

An Erratum to this article was published on 01 December 2003

Abstract

Ca2+-regulated gene transcription is essential to diverse physiological processes, including the adaptive plasticity associated with learning. We found that basal synaptic input activates the NF-κB transcription factor by a pathway requiring the Ca2+/calmodulin-dependent kinase CaMKII and local submembranous Ca2+ elevation. The p65:p50 NF-κB form is selectively localized at synapses; p65-deficient mice have no detectable synaptic NF-κB. Activated NF-κB moves to the nucleus and could directly transmute synaptic signals into altered gene expression. Mice lacking p65 show a selective learning deficit in the spatial version of the radial arm maze. These observations suggest that long-term changes to adult neuronal function caused by synaptic stimulation can be regulated by NF-κB nuclear translocation and gene activation.

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Figure 1: Activation of NF-κB in hippocampal neurons and isolated synapses.
Figure 2: FRAP analysis of GFPp65 movement.
Figure 3: Ca2+-dependent pathway of NF-kB activation.
Figure 4: Radial arm maze performance in p65-wildtype and -deficient mice.

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Acknowledgements

We thank E. Schuman and U. Bayer for support, discussion and critical reading of the manuscript, H. Schulman and his laboratory for the antCNt peptide, and E. Brown, A. Hoffman, J. Pomerantz and other members of the D. Baltimore laboratory for support and suggestions. We thank E. Alcamo for creating the double-knockout mouse line TNFR1/p65, which was critical to our experiments, and M. Sanders for training and assistance with behavioral assays. This work was supported by a National Institute of Neurological Disorders and Stroke (NINDS) KO8 grant to M.K.M. and a National Institutes of Health (NIH) grant to D.B.

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Authors and Affiliations

  1. Division of Biology, MC204-31 California Institute of Technology, Pasadena, 91125, California, USA

    Mollie K Meffert, Jolene M Chang & David Baltimore

  2. Department of Psychology, 1285 Franz Hal, University of California Los Angeles, Los Angeles, 90095, California, USA

    Brian J Wiltgen & Michael S Fanselow

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Supplementary information

Supplementary Fig. 1.

Glutamate induces GFPp65 translocation in neurons but not glia. (a) 3D reconstruction from Z-stacked confocal images of a mature hippocampal neuron in culture expressing GFPp65 after biolistic transfection. Bath stimulation with glutamate (250 μM) for 3 min results in a decrease of peripheral fluorescence and a gain in nuclear fluorescence 40 min later (lower panel). Scale bar represents 10 μm. (b) A glial cell in culture expressing GFPp65 after biolistic transfection is challenged with increasing concentrations of glutamate. An hour was allowed to elapse following each stimulation during which time nuclear fluorescence did not detectably increase. (c) The same glial cell depicted in a and b was washed and rested for 2 h prior to TNF-α (10 ng / ml) challenge. Nuclear fluorescence was visible at 20 min following stimulation with peak fluorescence occurring 60 min after the TNF-α addition. (JPG 52 kb)

Supplementary Fig. 2.

p65-dependent transcription of IκBα following stimulation. The time course of IkBa induction is examined by ribonuclease protection analysis of total RNA from basal and stimulated cultures of TNFR-/-,p65-/- and TNFR-/-,p65+/+ mice (indicated by yellow and blue, respectively). Neurons were pharmacologically silenced (see Methods) to obtain consistent basal conditions and stimulated by depolarization with 60 mM KCl. IκBα expression was significantly induced in p65-wildtype cultures at both 3 and 5 hours following stimulation, with expression declining between 3 - 5 hours (p = 0.5, n = 4). Induction of IkBa was significantly less in p65-deficient compared to p65-wildtype cultures at time points indicated by an * (p = 0.5, n = 4). Error bars represent one s.e.m.. (GIF 18 kb)

Supplementary Fig. 3.

Induction from κB-Luc reporter is NF-κB-dependent. Mature hippocampal neuronal cultures from wildtype or p65-deficient (TNFR-/-, p65-/-) mice were co-infected with lentivirus containing either an intact NF-κB-reporter gene (κB-luc) or an NF-κB reporter gene containing a mutated κB consensus site and, to permit normalization, a constitutively expressed β-galactosidase. Data shown are averaged replicates from 4 independent assays. All cultures were stimulated with bicuculline (50 mM, + 4-aminopyridine 5 μM). Error bars represent one s.e.m.. (GIF 20 kb)

Supplementary Fig. 4.

NF-κB activity is similarly reduced in both hippocampus and striatum. EMSA of extracts from striatum and hippocampus of p65-deficient (TNFR-/-,p65-/-) mature adult mice demonstrates that both tissues show a loss of κB-binding by p65-containing dimers without differential upregulation of other NF-κB activity (compare lanes 8,10). In p65-wildtype (TNFR-/-,p65+/+) but not in p65-deficient mice, DOC treatment reveals the presence of latent p50:p65 and p65:p65 (compare lanes 2,7 to lanes 9,11). SS denotes supershifted bands. The open arrowhead indicates a band which may correspond to the previously reported brain-specific transcription factor, BETA, which can bind κB sequencesS3 (see Supplementary Methods); both BETA and p65:p65 appeared more prominently in extracts from mature (>3 months) than young adult mice (data not shown). (JPG 59 kb)

Supplementary Fig. 5.

Quadrant crossings in p65-wildtype and deficient mice. Crossings between quadrants made by mice placed individually in a novel open-cage environment were measured for 3 min. Exploratory crossings made by p65-deficient mice (TNFR-/-,p65-/-) compared to p65-wildtype siblings (TNFR-/-,p65+/+) were not significantly different (17.1 ± 1.6, 18.2 ± 1.5, n = 10 for each genotype). Error bars represent one s.e.m.. (GIF 13 kb)

Supplementary Methods (PDF 15 kb)

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Meffert, M., Chang, J., Wiltgen, B. et al. NF-κB functions in synaptic signaling and behavior. Nat Neurosci 6, 1072–1078 (2003). https://doi.org/10.1038/nn1110

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