Hoeffer Charles A, Tang Wei, Wong Helen, Santillan Arturo, Patterson Richard J, Martinez Luis A, Tejada-Simon Maria V, Paylor Richard, Hamilton Susan L, Klann Eric
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Neuron. 2008 Dec 10;60(5):832-45. doi: 10.1016/j.neuron.2008.09.037.
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. Electrophysiological 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.
FK506结合蛋白12（FKBP12）可结合免疫抑制剂FK506和雷帕霉素，并调节多种信号通路，包括雷帕霉素哺乳动物靶标（mTOR）信号通路。我们确定了小鼠中FKBP12基因的脑特异性破坏是否会改变mTOR信号通路、突触可塑性和记忆。在生物化学方面，FKBP12基因缺陷型小鼠的基础mTOR磷酸化、mTOR与雷帕霉素靶蛋白（Raptor）的相互作用以及p70核糖体蛋白S6激酶（S6K）磷酸化均增加。电生理实验表明，FKBP12缺陷与持久的海马长时程增强（LTP）增强有关。LTP增强对雷帕霉素有抗性，但对茴香霉素没有抗性，这表明翻译控制的改变参与了增强的突触可塑性。在行为方面，FKBP12条件性敲除（cKO）小鼠在包括水迷宫、Y迷宫反转任务和新物体识别测试在内的多项实验中表现出增强的情境恐惧记忆和自闭症/强迫症样的固执行为。我们的结果表明，FKBP12在调节mTOR-Raptor相互作用、LTP、记忆和固执行为中起关键作用。
