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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Bacterial Proteins / genetics
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Bicuculline / pharmacology
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Cells, Cultured
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Computational Biology
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Dendrites / physiology
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Dendritic Spines / drug effects
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Dendritic Spines / metabolism
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Disks Large Homolog 4 Protein
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Excitatory Amino Acid Antagonists / pharmacology
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Excitatory Postsynaptic Potentials / physiology
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Female
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GABA-A Receptor Antagonists / pharmacology
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Gene Expression Regulation, Developmental / genetics
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Gene Expression Regulation, Developmental / physiology*
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / pharmacology
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Guanylate Kinases
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Hippocampus / cytology
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism
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Luminescent Proteins / genetics
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Male
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Membrane Proteins / metabolism
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Mice
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Mutation / genetics
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Nerve Tissue Proteins / metabolism
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Neurogenesis / drug effects
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Neurogenesis / genetics
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Neurogenesis / physiology*
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Neuronal Plasticity / drug effects
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Neuronal Plasticity / physiology*
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Patch-Clamp Techniques
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Potassium Channels / genetics
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Potassium Channels / metabolism
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Potassium Channels, Sodium-Activated
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Pyramidal Cells / cytology*
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Synapses / drug effects
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Synapses / physiology*
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Time Factors
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Transfection / methods
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Valine / analogs & derivatives
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Valine / pharmacology
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Vesicular Inhibitory Amino Acid Transport Proteins / metabolism
Substances
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Bacterial Proteins
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Bsn protein, mouse
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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Excitatory Amino Acid Antagonists
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GABA-A Receptor Antagonists
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Intracellular Signaling Peptides and Proteins
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Kcnt2 protein, mouse
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Luminescent Proteins
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Membrane Proteins
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NF-kappa B
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Nerve Tissue Proteins
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Potassium Channels
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Potassium Channels, Sodium-Activated
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Vesicular Inhibitory Amino Acid Transport Proteins
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Viaat protein, mouse
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enhanced green fluorescent protein
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yellow fluorescent protein, Bacteria
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Green Fluorescent Proteins
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2-amino-5-phosphopentanoic acid
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Guanylate Kinases
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Valine
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Bicuculline