title: A requirement for nuclear factor-kappaB in developmental and plasticity-associated synaptogenesis.
abstract: Structural plasticity of dendritic spines and synapses is a fundamental mechanism governing neuronal circuits and may form an enduring basis for information storage in the brain. We find that the p65 subunit of the nuclear factor-κB (NF-κB) transcription factor, which is required for learning and memory, controls excitatory synapse and dendritic spine formation and morphology in murine hippocampal neurons. Endogenous NF-κB activity is elevated by excitatory transmission during periods of rapid spine and synapse development. During in vitro synaptogenesis, NF-κB enhances dendritic spine and excitatory synapse density and loss of endogenous p65 decreases spine density and spine head volume. Cell-autonomous function of NF-κB within the postsynaptic neuron is sufficient to regulate the formation of both presynaptic and postsynaptic elements. During synapse development in vivo, loss of NF-κB similarly reduces spine density and also diminishes the amplitude of synaptic responses. In contrast, after developmental synaptogenesis has plateaued, endogenous NF-κB activity is low and p65 deficiency no longer attenuates basal spine density. Instead, NF-κB in mature neurons is activated by stimuli that induce demand for new synapses, including estrogen and short-term bicuculline, and is essential for upregulating spine density in response to these stimuli. p65 is enriched in dendritic spines making local protein-protein interactions possible; however, the effects of NF-κB on spine density require transcription and the NF-κB-dependent regulation of PSD-95, a critical postsynaptic component. Collectively, our data define a distinct role for NF-κB in imparting transcriptional regulation required for the induction of changes to, but not maintenance of, excitatory synapse and spine density.
authors.affiliation: The Solomon H Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Matthew C H
authors.initials: MC
authors.lastname: Boersma
authors.forename: Erica C
authors.initials: EC
authors.lastname: Dresselhaus
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: De Biase
authors.forename: Anca B
authors.initials: AB
authors.lastname: Mihalas
authors.forename: Dwight E
authors.initials: DE
authors.lastname: Bergles
authors.forename: Mollie K
authors.initials: MK
authors.lastname: Meffert
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001426:Bacterial Proteins / Q000235:genetics; D001640:Bicuculline / Q000494:pharmacology; D002478:Cells, Cultured; D019295:Computational Biology; D003712:Dendrites / Q000502:physiology; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000494:pharmacology; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D000081033:Potassium Channels, Sodium-Activated; D017966:Pyramidal Cells / Q000166:cytology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; C498441:Bsn protein, mouse; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D018691:Excitatory Amino Acid Antagonists; D058787:GABA-A Receptor Antagonists; D047908:Intracellular Signaling Peptides and Proteins; C518649:Kcnt2 protein, mouse; D008164:Luminescent Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; C485184:enhanced green fluorescent protein; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins; C056639:2-amino-5-phosphopentanoic acid; D051528:Guanylate Kinases; D014633:Valine; D001640:Bicuculline