Department of Physiology and Pharmacology, The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York Downstate Health Sciences University, Brooklyn, New York, USA.
Department of Anesthesiology, State University of New York Downstate Health Sciences University, Brooklyn, New York, USA.
Eur J Neurosci. 2021 Oct;54(8):6795-6814. doi: 10.1111/ejn.15137. Epub 2021 Mar 28.
PKMζ is an autonomously active PKC isoform crucial for the maintenance of synaptic long-term potentiation (LTP) and long-term memory. Unlike other kinases that are transiently stimulated by second messengers, PKMζ is persistently activated through sustained increases in protein expression of the kinase. Therefore, visualizing increases in PKMζ expression during long-term memory storage might reveal the sites of its persistent action and thus the location of memory-associated LTP maintenance in the brain. Using quantitative immunohistochemistry validated by the lack of staining in PKMζ-null mice, we examined the amount and distribution of PKMζ in subregions of the hippocampal formation of wild-type mice during LTP maintenance and spatial long-term memory storage. During LTP maintenance in hippocampal slices, PKMζ increases in the pyramidal cell body and stimulated dendritic layers of CA1 for at least 2 hr. During spatial memory storage, PKMζ increases in CA1 pyramidal cells for at least 1 month, paralleling the persistence of the memory. During the initial expression of the memory, we tagged principal cells with immediate-early gene Arc promoter-driven transcription of fluorescent proteins. The subset of memory-tagged CA1 cells selectively increases expression of PKMζ during memory storage, and the increase persists in dendritic compartments within stratum radiatum for 1 month, indicating long-term storage of information in the CA3-to-CA1 pathway. We conclude that persistent increases in PKMζ trace the molecular mechanism of LTP maintenance and thus the sites of information storage within brain circuitry during long-term memory.
PKMζ 是一种自主激活的蛋白激酶 C 同工型，对维持突触长时程增强（LTP）和长时记忆至关重要。与其他被第二信使短暂激活的激酶不同，PKMζ 通过激酶蛋白表达的持续增加而持续激活。因此，在长时记忆存储过程中观察到 PKMζ 表达的增加，可能揭示其持续作用的部位，从而揭示大脑中与记忆相关的 LTP 维持的位置。我们使用定量免疫组织化学技术，通过 PKMζ 缺失小鼠缺乏染色的验证，检查了野生型小鼠海马结构各亚区在 LTP 维持和空间长时记忆存储过程中 PKMζ 的数量和分布。在海马切片的 LTP 维持过程中，PKMζ 在锥体神经元胞体和 CA1 的刺激树突层中至少增加 2 小时。在空间记忆存储过程中，PKMζ 在 CA1 锥体神经元中的增加至少持续 1 个月，与记忆的持久性平行。在记忆的初始表达过程中，我们使用即时早期基因 Arc 启动子驱动荧光蛋白转录标记主细胞。在记忆存储过程中，记忆标记的 CA1 细胞子集选择性地增加 PKMζ 的表达，这种增加在放射层的树突隔室中持续 1 个月，表明 CA3 到 CA1 通路中的信息长期存储。我们得出结论，PKMζ 的持续增加追踪了 LTP 维持的分子机制，从而追踪了长时记忆过程中大脑回路中信息存储的位置。
