Removal of FKBP12 Enhances mTOR-Raptor Interactions, LTP, Memory, and Perseverative/Repetitive Behavior
Removal of FKBP12 Enhances mTOR-Raptor Interactions, LTP, Memory, and Perseverative/Repetitive Behavior
复制标题
DOI：
10.1016/j.neuron.2008.09.037
复制
发表时间：
2008-12-11
期刊：
影响因子：
16.2
通讯作者：
Klann, Eric
中科院分区：
文献类型：
--
作者：
Hoeffer, Charles A.;Tang, Wei;Klann, Eric
FK506结合蛋白12(FKBP12)与免疫抑制药物FK506和雷帕霉素结合，调节多种信号通路，包括哺乳动物雷帕霉素靶标(MTOR)信号通路。我们确定了小鼠大脑中FKBP12基因的特异性破坏是否改变了mTOR信号、突触可塑性和记忆。在生化方面，FKBP12缺陷小鼠表现出基础mTOR磷酸化、mTOR-Raptor相互作用和p70 S6激酶(S6K)磷酸化增加。电生理实验表明，FKBP12缺乏与海马长时程增强(LTP)有关。LTP的增强对雷帕霉素有抵抗力，但对山奈霉素没有影响，提示翻译控制的改变参与了突触可塑性的增强。在行为学上，FKBP12条件性基因敲除(CKO)小鼠在包括水迷宫、Y迷宫反转任务和新对象识别测试在内的几个测试中显示出增强的情景恐惧记忆和自闭症/强迫症样坚持。我们的结果表明，FKBP12在mTOR-Raptor相互作用、LTP、记忆和持久力行为的调节中发挥着关键作用。
FK506-binding protein 12 (FKBP12) binds the immunosuppressant drugs FK506 and rapamycin and regulates several signaling pathways, including mammalian target of rapamycin (mTOR) signaling. We determined whether the brain-specific disruption of the FKBP12 gene in mice altered mTOR signaling, synaptic plasticity, and memory. Biochemically, the FKBP12-deficient mice displayed increases in basal mTOR phosphorylation, mTOR-Raptor interactions, and p70 S6 kinase (S6K) phosphorylation. Electro-physiological experiments revealed that FKBP12 deficiency was associated with an enhancement in long-lasting hippocampal long-term potentiation (LTP). The LTP enhancement was resistant to rapamycin, but not anisomycin, suggesting that altered translation control is involved in the enhanced synaptic plasticity. Behaviorally, FKBP12 conditional knockout (cKO) mice displayed enhanced contextual fear memory and autistic/obsessive-compulsive-like perseveration in several assays including the water maze, Y-maze reversal task, and the novel object recognition test. Our results indicate that FKBP12 plays a critical role in the regulation of mTOR-Raptor interactions, LTP, memory, and perseverative behaviors.