title: NF-kappaB/Rel regulates inhibitory and excitatory neuronal function and synaptic plasticity.
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-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.
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, CA 94141, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: O'Mahony
authors.forename: Jacob
authors.initials: J
authors.lastname: Raber
authors.forename: Mauricio
authors.initials: M
authors.lastname: Montano
authors.forename: Erik
authors.initials: E
authors.lastname: Foehr
authors.forename: Victor
authors.initials: V
authors.lastname: Han
authors.forename: Shao-ming
authors.initials: SM
authors.lastname: Lu
authors.forename: Hakju
authors.initials: H
authors.lastname: Kwon
authors.forename: Anthony
authors.initials: A
authors.lastname: LeFevour
authors.forename: Shikha
authors.initials: S
authors.lastname: Chakraborty-Sett
authors.forename: Warner C
authors.initials: WC
authors.lastname: Greene
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003071:Cognition / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D005968:Glutamate Decarboxylase / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000473:pathology; D020672:I-kappa B Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics; D017774:Long-Term Potentiation / Q000502:physiology*; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D009473:Neuronal Plasticity; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005968:Glutamate Decarboxylase; D018698:Glutamic Acid; D020672:I-kappa B Proteins; D007527:Isoenzymes; D000072000:NF-KappaB Inhibitor alpha; D012333:RNA, Messenger; D018091:Receptors, AMPA; D051996:Transcription Factor RelA; D005680:gamma-Aminobutyric Acid; C000606205:Nfkbia protein, mouse; C401141:glutamate decarboxylase 2