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

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 α (CaMKKα), which phosphorylates and activates both CaM kinase I (CaMKI) and CaMKIV, the output kinases of the cascade. We show that CaMKKα is dispensable for brain development and long-term potentiation in adult hippocampal CA1 synapses. We find that CaMKKα is required for hippocampus-dependent contextual fear memory, but not spatial memory, formation. Surprisingly, CaMKKα 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 CaMKKα, while in female mice, contextual fear conditioning induces down-regulation of hippocampal BDNF mRNA expression that does not require CaMKKα. Additionally, we demonstrate sex-independent up-regulation in hippocampal nerve growth factor-inducible gene B mRNA expression that does not require CaMKKα. Thus, we show that CaMKKα has a specific complex role in memory formation in males.

We thank L. Drinkwater, J. Garthwaite, S. Josselyn, S. Rose, J. Vernon, and C. H. Yeo for helpful discussions; M. Peters for CaMKKα null mutants for breeding; J. Jeyabalan for help with genotyping; H. Sakagami for antibodies; and the UK Human Genome Mapping Project Resource Centre for the PAC4 mouse genomic library.

This study was supported by the Wellcome Trust, a Human Frontier Science Young Investigator Award, and a Medical Research Council grant to K.P.G. L.R. and E.G. were supported by the Belgian National Fund for Scientific Research and the Queen Elisabeth Fund for Medical Research. L.R. is a research associate of the Belgian National Fund for Scientific Research. The ABI7000 PCR system used in this study was funded by the Elton John AIDS Foundation.