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A requirement for nuclear factor-kappaB in developmental and plasticity-associated synaptogenesis.

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.

Pubmed ID: 21471377 RIS Download

Mesh terms: Animals | Animals, Newborn | Bacterial Proteins | Bicuculline | Cells, Cultured | Computational Biology | Dendrites | Dendritic Spines | Excitatory Amino Acid Antagonists | Excitatory Postsynaptic Potentials | Female | GABA-A Receptor Antagonists | Gene Expression Regulation, Developmental | Green Fluorescent Proteins | Guanylate Kinases | Hippocampus | Humans | Intracellular Signaling Peptides and Proteins | Luminescent Proteins | Male | Membrane Proteins | Mice | Mutation | NF-kappa B | Nerve Tissue Proteins | Neurogenesis | Neuronal Plasticity | Patch-Clamp Techniques | Potassium Channels | Pyramidal Cells | Synapses | Time Factors | Transfection | Valine | Vesicular Inhibitory Amino Acid Transport Proteins

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Associated grants

  • Agency: NIMH NIH HHS, Id: R01 MH080740
  • Agency: NEI NIH HHS, Id: T32 EY017203
  • Agency: NIMH NIH HHS, Id: MH084020

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