Memory maintenance by PKMζ--an evolutionary perspective.
Memory maintenance by PKMζ--an evolutionary perspective.
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DOI：
10.1186/1756-6606-5-31
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发表时间：
2012-09-18
期刊：
影响因子：
3.6
通讯作者：
Sacktor TC
中科院分区：
文献类型：
--
作者：
Sacktor TC
长期记忆被认为是通过对调节行为的神经回路中突触传递的持续修改来维持的。因此，长时程增强(LTP)被广泛研究为持续增强突触强度的潜在生理学基础，从而可能维持记忆。虽然最初诱导LTP的分子机制已经被广泛描述，但持续保持增强的机制还没有。然而，最近发现了一种将LTP的维持和长期记忆的存储联系起来的候选分子机制。自主活性的非典型蛋白激酶C(APKC)亚型PKMζ的持续活性是维持LTP的必要条件和充分条件。此外，药物或显性负性抑制物阻断PKMζ活性，破坏了先前储存在多种神经回路中的长期记忆，包括海马区的空间和痕迹记忆，杏仁核底外侧的厌恶记忆，伏隔核的食欲记忆，背外侧纹状体的习性记忆，以及新皮质中的基本联系、灭绝和熟练的感觉运动记忆。在长时程增强和记忆形成过程中，PKMζ从头合成，作为一种结构性活性的激酶。这种记忆存储的分子机制在进化上是保守的。PKMζ的形成可能起源于5亿年前的寒武纪早期脊椎动物。在无脊椎动物中还发现了从aPKC形成持久活跃的PKM的其他机制，抑制这种非典型的PKM会扰乱无脊椎动物模型系统果蝇和海兔的长期记忆。相反，过表达PKMζ增强了苍蝇和啮齿动物的记忆。PKMζ通过维持突触后部位AMPA受体数量的增加来持续增强突触强度，这一机制可能已经从膜蛋白转运的一般功能进化到极化细胞的顶室。这种记忆机制可能具有适应性优势，因为它既是稳定的，也是可逆的，正如灭绝后经验依赖的PKMζ的下调和削弱学习行为的重新巩固阻断所证明的那样。因此，长时程增强的“工作端”PKMζ是进化上保守的分子机制的一个组成部分，用于持久而灵活地存储长期记忆。
Long-term memory is believed to be maintained by persistent modifications of synaptic transmission within the neural circuits that mediate behavior. Thus, long-term potentiation (LTP) is widely studied as a potential physiological basis for the persistent enhancement of synaptic strength that might sustain memory. Whereas the molecular mechanisms that initially induce LTP have been extensively characterized, the mechanisms that persistently maintain the potentiation have not. Recently, however, a candidate molecular mechanism linking the maintenance of LTP and the storage of long-term memory has been identified. The persistent activity of the autonomously active, atypical protein kinase C (aPKC) isoform, PKMζ, is both necessary and sufficient for maintaining LTP. Furthermore, blocking PKMζ activity by pharmacological or dominant negative inhibitors disrupts previously stored long-term memories in a variety of neural circuits, including spatial and trace memories in the hippocampus, aversive memories in the basolateral amygdala, appetitive memories in the nucleus accumbens, habit memory in the dorsal lateral striatum, and elementary associations, extinction, and skilled sensorimotor memories in the neocortex. During LTP and memory formation, PKMζ is synthesized de novo as a constitutively active kinase. This molecular mechanism for memory storage is evolutionarily conserved. PKMζ formation through new protein synthesis likely originated in early vertebrates ~500 million years ago during the Cambrian period. Other mechanisms for forming persistently active PKM from aPKC are found in invertebrates, and inhibiting this atypical PKM disrupts long-term memory in the invertebrate model systems Drosophila melanogaster and Aplysia californica. Conversely, overexpressing PKMζ enhances memory in flies and rodents. PKMζ persistently enhances synaptic strength by maintaining increased numbers of AMPA receptors at postsynaptic sites, a mechanism that might have evolved from the general function of aPKC in trafficking membrane proteins to the apical compartment of polarized cells. This mechanism of memory may have had adaptive advantages because it is both stable and reversible, as demonstrated by the downregulation of experience-dependent, long-term increases in PKMζ after extinction and reconsolidation blockade that attenuate learned behavior. Thus, PKMζ, the “working end” of LTP, is a component of an evolutionarily conserved molecular mechanism for the persistent, yet flexible storage of long-term memory.
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