NF-κB/Rel regulates inhibitory and excitatory neuronal function and synaptic plasticity

Alison O'Mahony, Jacob Raber, Mauricio Montano, Erik Foehr, Victor Han, Shao Ming Lu, Hakju Kwon, Anthony LeFevour, Shikha Chakraborty-Sett, Warner C. Greene

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

Changes in synaptic plasticity required for memory formation are dynamically regulated through opposing excitatory and inhibitory neurotransmissions. To explore the potential contribution of NF-κB/Rel to these processes, we generated transgenic mice conditionally expressing a potent NF-κB/Rel inhibitor termed IκBα superrepressor (IκBα-SR). Using the prion promoter-enhancer, IκBα-SR is robustly expressed in inhibitory GABAergic interneurons and, at lower levels, in excitatory neurons but not in glia. This neuronal pattern of IκBα-SR expression leads to decreased expression of glutamate decarboxylase 65 (GAD65), the enzyme required for synthesis of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA) in GABAergic interneurons. IκBα-SR expression also results in diminished basal GluR1 levels and impaired synaptic strength (input/output function), both of which are fully restored following activity-based task learning. Consistent with diminished GAD65-derived inhibitory tone and enhanced excitatory firing, IκBα-SR+ mice exhibit increased late-phase long-term potentiation, hyperactivity, seizures, increased exploratory activity, and enhanced spatial learning and memory. IκBα-SR+ neurons also express higher levels of the activity-regulated, cytoskeleton-associated (Arc) protein, consistent with neuronal hyperexcitability. These findings suggest that NF-κB/Rel transcription factors act as pivotal regulators of activity-dependent inhibitory and excitatory neuronal function regulating synaptic plasticity and memory.

Original languageEnglish (US)
Pages (from-to)7283-7298
Number of pages16
JournalMolecular and cellular biology
Volume26
Issue number19
DOIs
StatePublished - Oct 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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