Ca2+/calmodulin kinase kinase at is dispensable for brain development but is required for distinct memories in male, though not in female, mice
Ca2+/calmodulin kinase kinase at is dispensable for brain development but is required for distinct memories in male, though not in female, mice
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DOI：
10.1128/mcb.01221-06
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发表时间：
2006-12-01
影响因子：
5.3
通讯作者：
Giese, K. Peter
中科院分区：
文献类型：
--
作者：
Mizuno, Keiko;Ris, Laurence;Giese, K. Peter
在神经元中，Ca 2 +/钙调蛋白（CaM）激酶级联将Ca 2+信号转导到基因转录中。已知CaM激酶级联对大脑发育以及成人大脑中的记忆形成是重要的，尽管一些级联成员的功能仍然未知。在这里，我们已经产生了无效和亚纯型突变体，以研究CaM激酶激酶α（CaMKK α）的生理作用，磷酸化和激活CaM激酶I（CaMKI）和CaMKIV，级联的输出激酶。我们发现，CaMKK α是大脑发育和长时程增强成人海马CA 1突触。我们发现，CaMKK α是必要的校园依赖的上下文恐惧记忆，但不是空间记忆，形成。令人惊讶的是，CaMKK α对男性的情境恐惧记忆形成很重要，但对女性则不然。我们发现，在雄性小鼠中，背景恐惧条件反射诱导上调海马脑源性神经营养因子（BDNF）的mRNA表达的方式，需要CaMKK α，而在雌性小鼠中，背景恐惧条件反射诱导下调海马BDNF mRNA表达，不需要CaMKK α。此外，我们证明了海马神经生长因子诱导基因B mRNA表达的性别无关性上调，不需要CaMKK α。因此，我们表明，CaMKK α在男性记忆形成中具有特定的复杂作用。
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.