Abstract
Memory consolidation, which converts acquired information into long-term storage, is new protein synthesis-dependent. As protein synthesis is a dynamic process that is under the control of multiple translational mechanisms, however, it is still elusive how these mechanisms are recruited in response to learning for memory consolidation. Here we found that eukaryotic elongation factor-2 (eEF-2) was dramatically dephosphorylated within 0.5–2 hr in the hippocampus and amygdala of mice following training in a fear-conditioning test, whereas genome-wide microarrays did not reveal any significant change in the expression level of the mRNAs for translational machineries or their related molecules. Moreover, blockade of NMDA receptors with MK-801 immediately following the training significantly impeded both the post-training eEF-2 dephosphorylation and memory retention. Notably, with an elegant sophisticated transgenic strategy, we demonstrated that hippocampus-specific overexpression of eEF-2 kinase, a kinase that specifically phosphorylates and hence inactivates eEF-2, significantly inhibited protein synthesis in the hippocampus, and this effects was more robust during an “ongoing” protein synthesis process. As a result, late phase long-term potentiation (L-LTP) in the hippocampus and long-term hippocampus-dependent memory in the mice were significantly impaired, whereas short-term memory and long-term hippocampus-independent memory remained intact. These results reveal a novel translational underpinning for protein synthesis pertinent to memory consolidation in the mammalian brain.
Highlights
The process of learning and memory may be divided into several sequential steps, including acquisition, consolidation, storage, and retrieval [1,2]
In order to determine whether training in the fear-conditioning test (FCT) altered the expression of translational machineries or/and their related molecules in the brain regions that are critically involved in consolidating fear memory, genome-wide cDNA microarrays were used to screen gene expression profiles in the hippocampus, amygdala, and cortex
Similar results were observed in the amygdala and cortex, indicating that changes in the expression level of the mRNAs for the translational machineries and their related molecules are unlikely to be a mechanism that is pivotal for memory consolidation-associated protein synthesis
Summary
The process of learning and memory may be divided into several sequential steps, including acquisition, consolidation, storage, and retrieval [1,2]. To explore the molecular and neuronal mechanisms underlying memory consolidation is fundamental for our understanding of how acquired information is encoded in the brain and insightful for disclosing how longterm memory formation could be impaired even though the acquisition is normal. This is of particular interest, as this kind of mnemonic dysfunction is often observed in many pathological conditions and clinical entities such as abnormal aging, mental retardation, and an early stage of neurodegenerative disease such as Alzheimer’s disease [6,7,8]
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