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

We thank Stanley Prusiner (University of California, San Francisco) for supplying the Prp/tTa mice and Paul Worley (Johns Hopkins) for generously providing Arc antibodies. We also thank Bobby Benitez, JoDee Fish, Jorge Palop-Esteban, and Vikram Rao (Gladstone Institutes) for their technical expertise and helpful comments. We also thank members of the Greene laboratory, Lennart Mucke, Steven Finkbeiner, and Michael Cowley, for helpful discussions. We are very grateful to Tom MacMahon, Kevin Deitchman, and Robert Messing (Ernest Gallo Clinic and Research Center) for their collegiality and invaluable assistance with the radial arm maze. We thank Angela Rizk-Jackson and Timothy F. Pfankuch for their assistance with the behavioral testing. We thank John Carroll, Jack Hull, Stephen Gonzales, and Chris Goodfellow for assistance in the preparation of figures, Stephen Ordway and Gary Howard for editorial assistance, and Robin Givens and Sue Cammack for administrative support.

This work was supported by the J. David Gladstone Institutes (W.C.G.) and NIH grant AG 20904 (J.R.) and the Extramural Research Facilities Improvement Program Project (C06 RR018928).