Departments of Physiology & Pharmacology, Anesthesiology, and Neurology, Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.
Department of Pharmacology, University of California, Davis, Davis, CA 95615, USA.
Sci Signal. 2017 Nov 14;10(505):eaao2327. doi: 10.1126/scisignal.aao2327.
Elucidating the molecular mechanisms that maintain long-term memory is a fundamental goal of neuroscience. Accumulating evidence suggests that persistent signaling by the atypical protein kinase C (PKC) isoform protein kinase Mζ (PKMζ) might maintain synaptic long-term potentiation (LTP) and long-term memory. However, the role of PKMζ has been challenged by genetic data from PKMζ-knockout mice showing intact LTP and long-term memory. Moreover, the PKMζ inhibitor peptide ζ inhibitory peptide (ZIP) reverses LTP and erases memory in both wild-type and knockout mice. Data from four papers using additional isoform-specific genetic approaches have helped to reconcile these conflicting findings. First, a PKMζ-antisense approach showed that LTP and long-term memory in PKMζ-knockout mice are mediated through a compensatory mechanism that depends on another ZIP-sensitive atypical isoform, PKCι/λ. Second, short hairpin RNAs decreasing the amounts of individual atypical isoforms without inducing compensation disrupted memory in different temporal phases. PKCι/λ knockdown disrupted short-term memory, whereas PKMζ knockdown specifically erased long-term memory. Third, conditional PKCι/λ knockout induced compensation by rapidly activating PKMζ to preserve short-term memory. Fourth, a dominant-negative approach in the model system revealed that multiple PKCs form PKMs to sustain different types of long-term synaptic facilitation, with atypical PKM maintaining synaptic plasticity similar to LTP. Thus, under physiological conditions, PKMζ is the principal PKC isoform that maintains LTP and long-term memory. PKCι/λ can compensate for PKMζ, and because other isoforms could also maintain synaptic facilitation, there may be a hierarchy of compensatory mechanisms maintaining memory if PKMζ malfunctions.
阐明维持长期记忆的分子机制是神经科学的一个基本目标。越来越多的证据表明，非典型蛋白激酶 C（PKC）同工型蛋白激酶 Mζ（PKMζ）的持续信号可能维持突触长时程增强（LTP）和长期记忆。然而，PKMζ 的作用受到来自 PKMζ 敲除小鼠的遗传数据的挑战，这些数据显示 LTP 和长期记忆完好无损。此外，PKMζ 抑制剂肽 ζ 抑制肽（ZIP）在野生型和敲除小鼠中逆转 LTP 并消除记忆。使用其他同工型特异性遗传方法的四份数据有助于调和这些相互矛盾的发现。首先，PKMζ 反义方法表明，PKMζ 敲除小鼠中的 LTP 和长期记忆是通过一种依赖于另一种对 ZIP 敏感的非典型同工型 PKCι/λ 的补偿机制介导的。其次，降低单个非典型同工型数量而不诱导补偿的短发夹 RNA 扰乱了不同时间阶段的记忆。PKCι/λ 敲低破坏了短期记忆，而 PKMζ 敲低特异性地消除了长期记忆。第三，条件性 PKCι/λ 敲除通过快速激活 PKMζ来诱导补偿，以维持短期记忆。第四，在模型系统中的显性负性方法表明，多种 PKC 形成 PKMs 以维持不同类型的长时突触易化，其中非典型 PKM 维持类似于 LTP 的突触可塑性。因此，在生理条件下，PKMζ 是维持 LTP 和长期记忆的主要 PKC 同工型。PKCι/λ 可以补偿 PKMζ，如果 PKMζ 功能失调，其他同工型也可能维持突触易化，因此可能存在维持记忆的补偿机制层次结构。
