NF-kappaB/Rel regulates inhibitory and excitatory neuronal function and synaptic plasticity.
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.
O'Mahony
Alison
A
Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, CA 94141, USA.
Raber
Jacob
J
Montano
Mauricio
M
Foehr
Erik
E
Han
Victor
V
Lu
Shao-ming
SM
Kwon
Hakju
H
LeFevour
Anthony
A
Chakraborty-Sett
Shikha
S
Greene
Warner C
WC
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
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