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 Ca 2؉ /calmodulin (CaM) kinase cascade transduces Ca 2؉ 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.

The roles of protein kinases in learning and memory

“…CaMKKb KO mice have impaired CREB activation during spatial memory formation and deficits in LTM, but not STM, after training in the social transmission of food preferences task (Peters et al 2003). CaMKKa KO mice have deficits in contextual fear LTM as well as conditioninginduced CaMKIV activation, CREB phosphorylation, and transcription of the brain-derived neurotrophic factor (BDNF) gene (Blaeser et al 2006;Mizuno et al 2006). Furthermore, pharmacological inhibition of CaMKKa/b impairs CaMKIa activation as well as object recognition LTM (Tinsley et al 2012).…”

A role for the CAMKK pathway in visual object recognition memory

“…There is increasing evidence that the CAMKK pathway plays an important role in memory. CAMKKα mutant mice show impaired fear memory (Blaeser et al, 2006;Mizuno et al, 2006) and CAMKKβ mutant mice exhibit impaired spatial memory formation (Peters et al, 2003). Additionally, pharmacological inhibition of CAMKK has been shown to impair induction of long-term potentiation (LTP) in the hippocampus (Schmitt et al, 2005).…”

Sex-dependent up-regulation of two splicing factors, Psf and Srp20, during hippocampal memory formation

“…The great majority of transcriptional studies on hippocampal LTM formation in rodents focus exclusively on males or disregard sex effects by analyzing male and female data together. While many behaviorally induced transcriptional events do not differ between the sexes, as is the case of expression of nerve growth factor-inducible gene B (Ngfi-b) , increasing lines of evidence suggest sex differences in transcription underlying hippocampusdependent LTM formation (Kudo et al 2004;Hebda-Bauer et al 2005;Mizuno et al 2006Mizuno et al , 2007.…”

“…Our previous work demonstrated an unexpected malespecific role of the CaMKKs in hippocampal LTM formation (Peters et al 2003;Mizuno et al 2006Mizuno et al , 2007. In male mice, CaMKK␣ is required for contextual fear LTM formation as well as the conditioning-induced activation of the transcription factor cAMPresponsive element binding protein (CREB) and transcription of the brain-derived neurotrophic factor (Bdnf) (Blaeser et al 2006;Mizuno et al 2006).…”