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Nature:此前公认的记忆形成模式”PKMζ“遭否定

Nature:此前公认的记忆形成模式”PKMζ“遭否定 PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory

约翰霍普金斯大学(Johns Hopkins University)研究人员近日进行了一项研究,研究结果显示公认的长期记忆形成模式(长期记忆形成取决于大脑中的某种单一酶)并不准确。这项新研究发表于近期《自然》杂志上。该研究发现,没有这种酶的小鼠实际上依然能像普通小鼠那样形成长期记忆。

2006年,托德-萨克特(Todd Sacktor)博士带领的研究队伍曾提出,长期记忆形成过程的关键是他们发现的一种被称为“PKMζ”的单一酶。他们还研制出了似乎只能抑制PKMζ的ZIP分子,引起了广泛关注。

之后许多有关PKMζ和ZIP的论文发表了,但没有任何一个人知道PKMζ对什么起作用。约翰霍普金斯大学医学院神经系统科学系教授理查德-胡格尼尔(Richard Huganir)和他的同事们决定研究PKMζ如何作用,希望能从中知道记忆是如何储存和保持的。

为了进行目前的研究,休加尼尔团队的成员莱诺拉·沃尔克和另一名研究人员培育出了缺乏PKMζ的老鼠,目的在于将该老鼠的突触和正常老鼠的突触进行对比,以期发现有关“PKMζ如何工作”的线索。研究结果显示,缺乏PKMζ老鼠大脑突触对于记忆消除ZIP分子的反应和正常老鼠大脑突触的反应一样。”研究人员又培育出了一种PKMζ基因功能正常但只要服用某种药物该基因就可被抑制的老鼠。然而,这种老鼠大脑突触对刺激的反应和正常老鼠的无异。

研究人员称,这就意味着尽管PKMζ在记忆形成过程中可能发挥了一些作用,但它并非长期记忆形成关键。沃尔克说:“我们不知道ZIP究竟对什么物质造成了影响。找到它作用的物质是非常重要的,那样我们才能在分子水平理解突触是如何加强的,以及在对刺激作出反应时,记忆是如何形成的。”

了解更多:

PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory

doi:10.1038/nature11802

Long-term potentiation (LTP), a well-characterized form of synaptic plasticity, has long been postulated as a cellular correlate of learning and memory. Although LTP can persist for long periods of time, the mechanisms underlying LTP maintenance, in the midst of ongoing protein turnover and synaptic activity, remain elusive. Sustained activation of the brain-specific protein kinase C (PKC) isoform protein kinase M-ζ (PKM-ζ) has been reported to be necessary for both LTP maintenance and long-term memory. Inhibiting PKM-ζ activity using a synthetic zeta inhibitory peptide (ZIP) based on the PKC-ζ pseudosubstrate sequence reverses established LTP in vitro and in vivo. More notably, infusion of ZIP eliminates memories for a growing list of experience-dependent behaviours, including active place avoidance, conditioned taste aversion, fear conditioning and spatial learning. However, most of the evidence supporting a role for PKM-ζ in LTP and memory relies heavily on pharmacological inhibition of PKM-ζ by ZIP. To further investigate the involvement of PKM-ζ in the maintenance of LTP and memory, we generated transgenic mice lacking PKC-ζ and PKM-ζ. We find that both conventional and conditional PKC-ζ/PKM-ζ knockout mice show normal synaptic transmission and LTP at Schaffer collateral–CA1 synapses, and have no deficits in several hippocampal-dependent learning and memory tasks. Notably, ZIP still reverses LTP in PKC-ζ/PKM-ζ knockout mice, indicating that the effects of ZIP are independent of PKM-ζ.

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