Ca2+/calmodulin kinase kinase alpha is dispensable for brain development but is required for distinct memories in male, though not in female, mice

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