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Mol. Cell. Biol. 26 (23): 9094-9104

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

Ca2+/Calmodulin Kinase Kinase {alpha} Is Dispensable for Brain Development but Is Required for Distinct Memories in Male, though Not in Female, Mice{triangledown}

Keiko Mizuno,1 Laurence Ris,2 Amelia Sánchez-Capelo,1 Emile Godaux,2, and K. Peter Giese1,{dagger}*

Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom,1 Department of Neurosciences, University of Mons—Hainaut, 7000 Mons, Belgium2

Received for publication 6 July 2006. Revision received 12 September 2006. Accepted for publication 18 September 2006.

Abstract: In neurons, the Ca2+/calmodulin (CaM) kinase cascade transduces Ca2+ signaling into gene transcription. The CaM kinase cascade is known to be important for brain development as well as memory formation in adult brain, although the functions of some cascade members remain unknown. Here we have generated null and hypomorphic mutants to study the physiological role of CaM kinase kinase {alpha} (CaMKK{alpha}), which phosphorylates and activates both CaM kinase I (CaMKI) and CaMKIV, the output kinases of the cascade. We show that CaMKK{alpha} is dispensable for brain development and long-term potentiation in adult hippocampal CA1 synapses. We find that CaMKK{alpha} is required for hippocampus-dependent contextual fear memory, but not spatial memory, formation. Surprisingly, CaMKK{alpha} is important for contextual fear memory formation in males but not in females. We show that in male mice, contextual fear conditioning induces up-regulation of hippocampal mRNA expression of brain-derived neurotrophic factor (BDNF) in a way that requires CaMKK{alpha}, while in female mice, contextual fear conditioning induces down-regulation of hippocampal BDNF mRNA expression that does not require CaMKK{alpha}. Additionally, we demonstrate sex-independent up-regulation in hippocampal nerve growth factor-inducible gene B mRNA expression that does not require CaMKK{alpha}. Thus, we show that CaMKK{alpha} has a specific complex role in memory formation in males.

* Corresponding author. Present address: Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom. E-mail: peter.giese{at}

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

{dagger} Present address: Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom.

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