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Molecular and Cellular Biology, August 2006, p. 5908-5920, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00269-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Synaptic Plasticity Deficits and Mild Memory Impairments in Mouse Models of Chronic Granulomatous Disease

Kenneth T. Kishida,1 Charles A. Hoeffer,2 Daoying Hu,2 Maryland Pao,3 Steven M. Holland,4 and Eric Klann1,2*

Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030,1 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030,2 Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892,3 Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 208924

Received 13 February 2006/ Returned for modification 13 March 2006/ Accepted 15 May 2006

Reactive oxygen species (ROS) are required in a number of critical cellular signaling events, including those underlying hippocampal synaptic plasticity and hippocampus-dependent memory; however, the source of ROS is unknown. We previously have shown that NADPH oxidase is required for N-methyl-D-aspartate (NMDA) receptor-dependent signal transduction in the hippocampus, suggesting that NADPH oxidase may be required for NMDA receptor-dependent long-term potentiation (LTP) and hippocampus-dependent memory. Herein we present the first evidence that NADPH oxidase is involved in hippocampal synaptic plasticity and memory. We have found that pharmacological inhibitors of NADPH oxidase block LTP. Moreover, mice that lack the NADPH oxidase proteins gp91phox and p47phox, both of which are mouse models of human chronic granulomatous disease (CGD), also lack LTP. We also found that the gp91phox and p47phox mutant mice have mild impairments in hippocampus-dependent memory. The gp91phox mutant mice exhibited a spatial memory deficit in the Morris water maze, and the p47phox mutant mice exhibited impaired context-dependent fear memory. Taken together, our results are consistent with NADPH oxidase being required for hippocampal synaptic plasticity and memory and are consistent with reports of cognitive dysfunction in patients with CGD.

* Corresponding author. Mailing address: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, One Baylor Plaza BCM 335, Houston, TX 77030. Phone: (713) 798-5630. Fax: (713) 798-3475. E-mail: eklann{at}bcm.tmc.edu.

Molecular and Cellular Biology, August 2006, p. 5908-5920, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00269-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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