FoxO6 regulates memory consolidation and synaptic function
FoxO6 regulates memory consolidation and synaptic function
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DOI：
10.1101/gad.208926.112
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发表时间：
2012-12-15
影响因子：
10.5
通讯作者：
Brunet, Anne
中科院分区：
文献类型：
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作者：
Salih, Dervis A. M.;Rashid, Asim J.;Brunet, Anne
众所周知，FoxO转录因子家族可以延缓胰岛素/IGF(胰岛素样生长因子)信号通路下游的衰老。最近在哺乳动物中发现的FoxO亚型FoxO6在成年海马体中高度丰富。然而，FoxO因素在认知中的重要性在很大程度上是未知的。在这里，我们产生了缺乏FoxO6的小鼠，发现这些小鼠表现出正常的学习能力，但在情景恐惧条件反射和新对象识别方面记忆巩固受到损害。通过将病毒立体定向注射到成年野生型小鼠的海马区，我们发现成年海马区的FoxO6活性是记忆巩固所必需的。全基因组方法显示，FoxO6在海马体学习时调节涉及突触功能的基因程序。在体外和体内，FoxO6缺乏都会导致海马神经元树突棘密度降低。因此，FoxO6可能通过调节协调海马区神经元连接的程序来促进记忆巩固，这可能对年龄相关性的生理性和病理性记忆衰退具有重要意义。
The FoxO family of transcription factors is known to slow aging downstream from the insulin/IGF (insulin-like growth factor) signaling pathway. The most recently discovered FoxO isoform in mammals, FoxO6, is highly enriched in the adult hippocampus. However, the importance of FoxO factors in cognition is largely unknown. Here we generated mice lacking FoxO6 and found that these mice display normal learning but impaired memory consolidation in contextual fear conditioning and novel object recognition. Using stereotactic injection of viruses into the hippocampus of adult wild-type mice, we found that FoxO6 activity in the adult hippocampus is required for memory consolidation. Genome-wide approaches revealed that FoxO6 regulates a program of genes involved in synaptic function upon learning in the hippocampus. Consistently, FoxO6 deficiency results in decreased dendritic spine density in hippocampal neurons in vitro and in vivo. Thus, FoxO6 may promote memory consolidation by regulating a program coordinating neuronal connectivity in the hippocampus, which could have important implications for physiological and pathological age-dependent decline in memory.