Unit on the Genetics of Cognition and Behavior, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Neurosci. 2010 Feb 17;30(7):2582-94. doi: 10.1523/JNEUROSCI.3971-09.2010.
Protein synthesis inhibitor antibiotics are widely used to produce amnesia, and have been recognized to inhibit general or global mRNA translation in the basic translational machinery. For instance, anisomycin interferes with protein synthesis by inhibiting peptidyl transferase or the 80S ribosomal function. Therefore, de novo general or global protein synthesis has been thought to be necessary for long-term memory formation. However, it is unclear which mode of translation-gene-specific translation or general/global translation-is actually crucial for the memory consolidation process in mammalian brains. Here, we generated a conditional transgenic mouse strain in which double-strand RNA-dependent protein kinase (PKR)-mediated phosphorylation of eIF2alpha, a key translation initiation protein, was specifically increased in hippocampal CA1 pyramidal cells by the chemical inducer AP20187. Administration of AP20187 significantly increased activating transcription factor 4 (ATF4) translation and concomitantly suppressed CREB-dependent pathways in CA1 cells; this led to impaired hippocampal late-phase LTP and memory consolidation, with no obvious reduction in general translation. Conversely, inhibition of general translation by low-dose anisomycin failed to block hippocampal-dependent memory consolidation. Together, these results indicated that CA1-restricted genetic manipulation of particular mRNA translations is sufficient to impair the consolidation and that consolidation of memories in CA1 pyramidal cells through eIF2alpha dephosphorylation depends more on transcription/translation of particular genes than on overall levels of general translation. The present study sheds light on the critical importance of gene-specific translations for hippocampal memory consolidation.
蛋白合成抑制剂类抗生素被广泛用于产生健忘症，并且已经被证实可以抑制基本翻译机制中的一般或全局 mRNA 翻译。例如，放线菌酮通过抑制肽基转移酶或 80S 核糖体功能来干扰蛋白合成。因此，新的一般或全局蛋白合成被认为是长时记忆形成所必需的。然而，对于哺乳动物大脑中的记忆巩固过程，哪种翻译模式——基因特异性翻译还是全局/整体翻译——实际上是至关重要的，目前还不清楚。在这里，我们通过化学诱导剂 AP20187 生成了一种条件性转基因小鼠品系，在这种品系中，双链 RNA 依赖性蛋白激酶 (PKR) 介导的翻译起始蛋白 eIF2alpha 的磷酸化可在海马 CA1 锥体神经元中特异性增加。AP20187 的给药显著增加了 CA1 细胞中的激活转录因子 4 (ATF4) 翻译，并伴随 CREB 依赖性途径的抑制；这导致海马体晚期长时程增强和记忆巩固受损，而一般翻译没有明显减少。相反，低剂量放线菌酮抑制一般翻译未能阻断海马体依赖性记忆巩固。总之，这些结果表明，CA1 区特定 mRNA 翻译的遗传操作足以损害巩固过程，并且通过 eIF2alpha 去磷酸化，CA1 锥体神经元中的记忆巩固更依赖于特定基因的转录/翻译，而不是一般翻译的总体水平。本研究揭示了基因特异性翻译对海马体记忆巩固的至关重要性。
