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eIF2α通过兴奋性和生长抑制神经元调控记忆巩固
2020-10-10 13:55

加拿大麦吉尔大学Nahum Sonenberg、Vijendra Sharma小组的最新研究发现eIF2α通过兴奋性和生长抑制素神经元调控记忆巩固。这一研究成果于2020年10月7日在线发表在国际学术期刊《自然》上。

研究人员利用分子遗传学来剖析综合应激反应(ISR)调控认知过程的神经回路。研究发现,学习减少了海马兴奋性神经元和海马抑制性神经元(表达生长抑制素,但不表达小白蛋白)中eIF2α的磷酸化。

此外,在兴奋性或生长抑制素表达(但非小白蛋白表达)的抑制性神经元中p-eIF2α的缺失增加了mRNA的翻译,增强了突触可塑性并增强了长时记忆。因此,eIF2α依赖的mRNA翻译通过兴奋性和生长抑素表达的抑制性神经元的自主机制调控记忆巩固。

据介绍,学习和记忆的重要法则是促进长期记忆形成的分子转换。在整合新记忆的过程中,蛋白稳态的调控是关键限速步骤。增强记忆力最有效和最普遍的方法是调节受翻译起始因子eIF2调控的蛋白质合成。eIF2 α-亚基(p-eIF2α)的磷酸化是ISR的主要成分,损害了啮齿动物和鸟类长期记忆的形成。相比之下,通过突变eIF2α磷酸化位点来抑制ISR,从基因和药理上抑制ISR激酶或通过ISR抑制剂ISRIB模拟还原态p-eIF2α,可以增强健康和疾病个体的长期记忆。

附:英文原文

Title: eIF2α controls memory consolidation via excitatory and somatostatin neurons

Author: Vijendra Sharma, Rapita Sood, Abdessattar Khlaifia, Mohammad Javad Eslamizade, Tzu-Yu Hung, Danning Lou, Azam Asgarihafshejani, Maya Lalzar, Stephen J. Kiniry, Matthew P. Stokes, Noah Cohen, Alissa J. Nelson, Kathryn Abell, Anthony P. Possemato, Shunit Gal-Ben-Ari, Vinh T. Truong, Peng Wang, Adonis Yiannakas, Fatemeh Saffarzadeh, A. Claudio Cuello, Karim Nader, Randal J. Kaufman, Mauro Costa-Mattioli, Pavel V. Baranov, Albert Quintana, Elisenda Sanz, Arkady Khoutorsky, Jean-Claude Lacaille, Kobi Rosenblum, Nahum Sonenberg

Issue&Volume: 2020-10-07

Abstract: An important tenet of learning and memory is the notion of a molecular switch that promotes the formation of long-term memory1,2,3,4. The regulation of proteostasis is a critical and rate-limiting step in the consolidation of new memories5,6,7,8,9,10. One of the most effective and prevalent ways to enhance memory is by regulating the synthesis of proteins controlled by the translation initiation factor eIF211. Phosphorylation of the α-subunit of eIF2 (p-eIF2α), the central component of the integrated stress response (ISR), impairs long-term memory formation in rodents and birds11,12,13. By contrast, inhibiting the ISR by mutating the eIF2α phosphorylation site, genetically11 and pharmacologically inhibiting the ISR kinases14,15,16,17, or mimicking reduced p-eIF2α with the ISR inhibitor ISRIB11, enhances long-term memory in health and disease18. Here we used molecular genetics to dissect the neuronal circuits by which the ISR gates cognitive processing. We found that learning reduces eIF2α phosphorylation in hippocampal excitatory neurons and a subset of hippocampal inhibitory neurons (those that express somatostatin, but not parvalbumin). Moreover, ablation of p-eIF2α in either excitatory or somatostatin-expressing (but not parvalbumin-expressing) inhibitory neurons increased general mRNA translation, bolstered synaptic plasticity and enhanced long-term memory. Thus, eIF2α-dependent mRNA translation controls memory consolidation via autonomous mechanisms in excitatory and somatostatin-expressing inhibitory neurons.

DOI: 10.1038/s41586-020-2805-8

Source: https://www.nature.com/articles/s41586-020-2805-8

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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