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Molecular and Cellular Biology, October 2006, p. 7283-7298, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.00510-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

NF-{kappa}B/Rel Regulates Inhibitory and Excitatory Neuronal Function and Synaptic Plasticity

Alison O'Mahony,1,{dagger} Jacob Raber,3,4,5,{dagger} Mauricio Montano,1,{dagger} Erik Foehr,1,{dagger},{ddagger} Victor Han,5 Shao-ming Lu,6 Hakju Kwon,1,§ Anthony LeFevour,3 Shikha Chakraborty-Sett,7 and Warner C. Greene1,2*

Gladstone Institute of Virology and Immunology,1 Departments of Medicine and Microbiology and Immunology, University of California, San Francisco, California 94141,2 Departments of Behavioral Neuroscience,3 Neurology,4 Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon 97239,5 Department of Neurology, Center for Aging and Developmental Biology,6 Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 146427

Received 22 March 2006/ Returned for modification 20 April 2006/ Accepted 13 July 2006

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.

* Corresponding author. Mailing address: Gladstone Institute of Virology and Immunology, University of California, San Francisco, 1650 Owens St., San Francisco, CA 94158. Phone: (415) 734-4804. Fax: (415) 355-0153. E-mail: wgreene{at}gladstone.ucsf.edu.

{dagger} A.O., J.R., M.M., and E.F. contributed equally to this work.

{ddagger} Present address: BioMarin Pharmaceutical, 105 Digital Drive, Novato, CA 94949.

§ Present address: PDL BioPharma, Inc., 34801 Campus Drive, Fremont, CA 94555.

Molecular and Cellular Biology, October 2006, p. 7283-7298, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.00510-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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