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eIF2a controls memory consolidation via excitatory and somatostatin neurons

机译：EIF2A通过兴奋和生长抑制素神经元控制内存整合

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摘要

Stimulation of de novo protein synthesis in both excitatory and inhibitory, somatostatin-expressing neurons in the mouse hippocampus enhances memory consolidation.An important tenet of learning and memory is the notion of a molecular switch that promotes the formation of long-term memory(1-4). The regulation of proteostasis is a critical and rate-limiting step in the consolidation of new memories(5-10). One of the most effective and prevalent ways to enhance memory is by regulating the synthesis of proteins controlled by the translation initiation factor eIF2(11). Phosphorylation of the alpha-subunit of eIF2 (p-eIF2 alpha), the central component of the integrated stress response (ISR), impairs long-term memory formation in rodents and birds(11-13). By contrast, inhibiting the ISR by mutating the eIF2 alpha phosphorylation site, genetically(11)and pharmacologically inhibiting the ISR kinases(14-17), or mimicking reduced p-eIF2 alpha with the ISR inhibitor ISRIB11, enhances long-term memory in health and disease(18). Here we used molecular genetics to dissect the neuronal circuits by which the ISR gates cognitive processing. We found that learning reduces eIF2 alpha phosphorylation in hippocampal excitatory neurons and a subset of hippocampal inhibitory neurons (those that express somatostatin, but not parvalbumin). Moreover, ablation of p-eIF2 alpha 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, eIF2 alpha-dependent mRNA translation controls memory consolidation via autonomous mechanisms in excitatory and somatostatin-expressing inhibitory neurons.
机译：在小鼠海马中表达生长抑制性和抑制性的脱蛋白合成的刺激增强了存储器整合。重要的学习和记忆的重要宗旨是促进长期记忆形成的分子开关的概念（1- 4）。蛋白质的调节是整合新存储器（5-10）的关键和速率限制步骤。增强记忆最有效和普遍的方法之一是通过调节由翻译引发因子EIF2（11）控制的蛋白质的合成。 EIF2（P-EIF2α）的α-亚基的磷酸化，综合应力响应（ISR）的中心分量（ISR），损害啮齿动物和鸟类中的长期记忆形成（11-13）。相比之下，通过突变EIF2α磷酸化位点，遗传（11）和药理学抑制ISR激酶（14-17），或用ISR抑制剂ISRIB11模仿降低的P-EIF2α，增强了健康的长期记忆和疾病（18）。在这里，我们使用的分子遗传学来描述ISR栅极认知处理的神经元电路。我们发现学习在海马兴奋性神经元和海马抑制神经元（表达生长抑制素，但不是Parvalbumise）中的eIF2α磷酸化。此外，在兴奋性或生长抑素表达（但不是帕瓦仑表达的）抑制性神经元中的P-EIF2α在兴奋剂或生长抑制素的α-翻译增加了一般MRNA平移，突触突触塑性和增强的长期记忆。因此，EIF2α-依赖性mRNA平移通过兴奋性和生长抑素表达抑制性神经元中的自主机制控制内存整合。

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  • 来源
    《Nature》 |2020年第7829期|412-416|共5页
  • 作者

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

  • 作者单位

    McGill Univ Dept Biochem Montreal PQ Canada|McGill Univ Rosalind & Morris Goodman Canc Res Ctr Montreal PQ Canada;

    McGill Univ Dept Biochem Montreal PQ Canada|McGill Univ Rosalind & Morris Goodman Canc Res Ctr Montreal PQ Canada;

    Univ Montreal Dept Neurosci Montreal PQ Canada;

    McGill Univ Dept Biochem Montreal PQ Canada|McGill Univ Rosalind & Morris Goodman Canc Res Ctr Montreal PQ Canada|Univ Montreal Dept Neurosci Montreal PQ Canada;

    McGill Univ Dept Biochem Montreal PQ Canada|McGill Univ Rosalind & Morris Goodman Canc Res Ctr Montreal PQ Canada;

    McGill Univ Dept Biochem Montreal PQ Canada|McGill Univ Rosalind & Morris Goodman Canc Res Ctr Montreal PQ Canada;

    Univ Montreal Dept Neurosci Montreal PQ Canada;

    Univ Haifa Bioinformat Serv Unit Fac Nat Sci Haifa Israel;

    Univ Coll Cork Sch Biochem & Cell Biol Cork T12 XF62 Ireland;

    Cell Signaling Technol Prote Div Danvers MA 01923 USA;

    McGill Univ Dept Biochem Montreal PQ Canada|McGill Univ Rosalind & Morris Goodman Canc Res Ctr Montreal PQ Canada;

    Cell Signaling Technol Prote Div Danvers MA 01923 USA;

    Cell Signaling Technol Prote Div Danvers MA 01923 USA;

    Cell Signaling Technol Prote Div Danvers MA 01923 USA;

    Univ Haifa Sagol Dept Neurobiol Haifa Israel;

    McGill Univ Dept Biochem Montreal PQ Canada|McGill Univ Rosalind & Morris Goodman Canc Res Ctr Montreal PQ Canada;

    McGill Univ Dept Biochem Montreal PQ Canada|McGill Univ Rosalind & Morris Goodman Canc Res Ctr Montreal PQ Canada;

    Univ Haifa Sagol Dept Neurobiol Haifa Israel;

    Univ Montreal Dept Neurosci Montreal PQ Canada;

    McGill Univ Dept Pharmacol & Therapeut Montreal PQ Canada;

    McGill Univ Dept Psychol Montreal PQ Canada;

    Sanford Burnham Prebys Med Discovery Inst Degenerat Dis Program La Jolla CA USA;

    Baylor Coll Med Dept Neurosci Houston TX 77030 USA;

    Cell Signaling Technol Prote Div Danvers MA 01923 USA|RAS Shemyakin & Ovchinnikov Inst Bioorgan Chem Moscow Russia;

    Univ Autonoma Barcelona Dept Cell Biol Physiol & Immunol Bellaterra Spain|Univ Autonoma Barcelona Neurosci Inst Bellaterra Spain;

    Univ Autonoma Barcelona Dept Cell Biol Physiol & Immunol Bellaterra Spain|Univ Autonoma Barcelona Neurosci Inst Bellaterra Spain;

    McGill Univ Dept Anesthesia Montreal PQ Canada|McGill Univ Fac Dent Montreal PQ Canada;

    Univ Montreal Dept Neurosci Montreal PQ Canada|Univ Montreal Ctr Interdisciplinary Res Brain & Learning Montreal PQ Canada;

    Univ Haifa Sagol Dept Neurobiol Haifa Israel|Univ Haifa Ctr Gene Manipulat Brain Haifa Israel;

    McGill Univ Dept Biochem Montreal PQ Canada|McGill Univ Rosalind & Morris Goodman Canc Res Ctr Montreal PQ Canada;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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