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Mol. Cell. Biol. 26 (23): 9105-9115

Copyright © 2006 by the American Society for Microbiology. All rights reserved.

Long-Term Memory Deficits in Pavlovian Fear Conditioning in Ca2+/Calmodulin Kinase Kinase {alpha}-Deficient Mice{triangledown}

Frank Blaeser,1 Matthew J. Sanders,2 Nga Truong,3 Shanelle Ko,4 Long Jun Wu,4 David F. Wozniak,5 Michael S. Fanselow,2 Min Zhuo,4, and Talal A. Chatila3*

Institute of Transfusion Medicine, University of Leipzig, Leipzig, Germany,1 Department of Psychology, University of California at Los Angeles, Los Angeles, California 90095,2 Department of Pediatrics, The David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095,3 Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8,4 Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 631105

Received for publication 6 August 2006. Revision received 29 August 2006. Accepted for publication 18 September 2006.

Abstract: Signaling by the Ca2+/calmodulin kinase (CaMK) cascade has been implicated in neuronal gene transcription, synaptic plasticity, and long-term memory consolidation. The CaM kinase kinase {alpha} (CaMKK{alpha}) isoform is an upstream component of the CaMK cascade whose function in different behavioral and learning and memory paradigms was analyzed by targeted gene disruption in mice. CaMKK{alpha} mutants exhibited normal long-term spatial memory formation and cued fear conditioning but showed deficits in context fear during both conditioning and long-term follow-up testing. They also exhibited impaired activation of the downstream kinase CaMKIV/Gr and its substrate, the transcription factor cyclic AMP-responsive element binding protein (CREB) upon fear conditioning. Unlike CaMKIV/Gr-deficient mice, the CaMKK{alpha} mutants exhibited normal long-term potentiation and normal levels of anxiety-like behavior. These results demonstrate a selective role for CaMKK{alpha} in contextual fear memory and suggest that different combinations of upstream and downstream components of the CaMK cascade may serve distinct physiological functions.

* Corresponding author. Mailing address: Department of Pediatrics, The David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1752. Phone: (310) 825-4125. Fax: (310) 206-4584. E-mail: Tchatila{at}

{triangledown} Published ahead of print on 2 October 2006.

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