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

Mol Cell Biol. 2006 Oct;26(19):7283-98. doi: 10.1128/MCB.00510-06.


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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Cognition / physiology
  • Gene Expression Regulation, Enzymologic
  • Glutamate Decarboxylase / genetics
  • Glutamic Acid / metabolism
  • Hippocampus / cytology
  • Hippocampus / pathology
  • I-kappa B Proteins / metabolism
  • Isoenzymes / genetics
  • Long-Term Potentiation / physiology*
  • Memory / physiology
  • Mice
  • Mice, Transgenic
  • NF-KappaB Inhibitor alpha
  • Neuronal Plasticity*
  • Neurons / cytology
  • Neurons / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, AMPA / metabolism
  • Synapses / metabolism*
  • Synaptic Transmission / physiology
  • Transcription Factor RelA / antagonists & inhibitors
  • Transcription Factor RelA / metabolism*
  • gamma-Aminobutyric Acid / metabolism


  • I-kappa B Proteins
  • Isoenzymes
  • Nfkbia protein, mouse
  • RNA, Messenger
  • Receptors, AMPA
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2
  • glutamate receptor ionotropic, AMPA 1