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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-B/Rel Regulates Inhibitory and Excitatory Neuronal Function and Synaptic Plasticity

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

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

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

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

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

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