Work

NF-κB/Rel Regulates Inhibitory and Excitatory Neuronal Function and Synaptic Plasticity

Year: 2006

Type: article

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.

Source: Molecular and Cellular Biology

DOI: 10.1128/mcb.00510-06