Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 26, Issue 19, Pages 7283-7298Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00510-06
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Funding
- NCRR NIH HHS [C06 RR018928] Funding Source: Medline
- NIA NIH HHS [AG 20904, R01 AG020904] Funding Source: Medline
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Changes in synaptic plasticity required for memory formation are dynamically regulated through opposing excitatory and inhibitory neurotransmissions. To explore the potential contribution of NF-kappa B/Rel to these processes, we generated transgenic mice conditionally expressing a potent NF-kappa B/Rel inhibitor termed I kappa B alpha superrepressor (I kappa B alpha-SR). Using the prion promoter-enhancer, I kappa B alpha-SR is robustly expressed in inhibitory GABAergic interneurons and, at lower levels, in excitatory neurons but not in glia. This neuronal pattern of I kappa B alpha-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. I kappa B alpha-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, I kappa B alpha-SR+ mice exhibit increased late-phase long-term potentiation, hyperactivity, seizures, increased exploratory activity, and enhanced spatial learning and memory. I kappa B alpha-SR+ neurons also express higher levels of the activity-regulated, cytoskeleton-associated (Arc) protein, consistent with neuronal hyperexcitability. These findings suggest that NF-kappa B/Rel transcription factors act as pivotal regulators of activity-dependent inhibitory and excitatory neuronal function regulating synaptic plasticity and memory.
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