The quest to unveil the mystery of memory and synaptic plasticity—for some years the domain of behavioral biologists and electrophysiologists—has led scientists squarely back to basic molecular biology. Because long-lasting memories require that new proteins be made, processes like translational regulation beg investigation. For its part, translation becomes initiated in response to mitogens and growth factors. In the February 6 Cell, researchers report how they trace back this chain of events by examining the role of mitogen-activated protein kinase (MAPK) in regulating translation in long-term memory. Led by Howard Hughes Medical Institute investigator Susumu Tonegawa, first author Raymond Kelleher and colleagues at MIT show that inhibition of MAPK signaling blocks the translation induced by neuronal activity, and in this way impairs long-term potentiation (LTP), a requirement for learning and memory.

MAPK, also known as extracellular-regulated kinase (ERK), is part of a signaling cascade, the physiological functions of which include the control of gene expression and programmed cell death. In neurons, this pathway is thought to be activated by elevated intracellular calcium and neurotrophins, hallmarks of synaptic activity and plasticity. MAPK/ERK is activated by MAPK/ERK kinase (MEK1), which some scientists have found to accumulate in neuronal nuclei in early stages of Alzheimer’s disease, triggering anomalous nuclear trafficking (Zhu et al., 2003). This and other evidence suggests that the MAPK/ERK pathway is dysregulated in AD and may contribute to its pathogenesis. As AD develops, synaptic dysfunction and LTP deficits precede overt neuronal degeneration.

Unlike short-term memory, consolidation of a memory for the long term requires new mRNA and protein synthesis. In the present study, the scientists asked whether MAPK/ERK signaling regulates translational events required for long-term memory storage and synaptic plasticity. They generated mice that expressed a dominant-negative form of MEK1 (dnMEK1) in the CA1 area of the hippocampus and neocortex, and used hippocampal slice recordings to confirm the kinase activity was eliminated. Testing for spatial reference memory in the Morris water maze (a hippocampus-dependent task), they found that the mutant mice took longer to find the hidden platform and spent less time than controls in the right quadrant, indicating a spatial memory impairment resulting from ERK inhibition. The dnMEK1 mice then underwent two fear conditioning tests—contextual (hippocampus-dependent) and cued (hippocampus-independent). The mutant mice exhibited normal short-term contextual memory in the former, and normal long-term non-contextual memory in the latter task. According to the authors, “These findings demonstrate a specific impairment in the protein-synthesis-dependent phase of hippocampus-dependent contextual memory in dnMEK1 mice.”

The paper also contains an electrophysiological analysis of the mice, done in hippocampal slices. Kelleher et al. found that basal synaptic transmission was normal in the mutants, and LTP induction using trains of tetanic stimulation only 20 seconds apart worked, as well. However, potentiation was unstable when the scientists tried to induce it with trains of tetanic (i.e., intense high-frequency) stimulation five minutes apart. In slices from the mutant mice, potentiation decayed almost to baseline levels by the end of recording, while control slices exhibited “late-LTP” (L-LTP, the version that depends on protein synthesis) for three hours after stimulation.

As past research has focused on L-LTP impairment by transcriptional inhibitors, Kelleher and colleagues compared them with translational inhibitors. Treating control hippocampal slices with the transcriptional inhibitor actinomycin-D did not affect L-LTP, but the translational inhibitor anisomycin did, and it did so in a progressive manner just like that observed previously in dnMEK1 slices. Furthermore, treating the mutant slices with these same two inhibitors caused no additional decrease in L-LTP, indicating that a defect was already present in the mutant slices. “This difference in the kinetic patterns of inhibition by actinomycin-D and anisomycin defines a transcription-independent, translation-dependent phase of L-LTP,” the authors conclude.

To probe whether ERK activation regulates neuronal protein synthesis, the researchers transfected cultured primary hippocampal neurons with synthetic mRNAs and stimulated them using three different methods. All modes of stimulation produced increases in synthetic mRNA translation, and the specific MEK inhibitor U1026 weakened this response. The researchers also examined the translation of endogenous transcripts in response to neuronal activity. Metabolic pulse labeling in hippocampal neurons indicated that neuronal activity facilitated the phosphorylation of key translation initiation factors, which could be inhibited by U1026. What’s more, ERK-dependent stimulation yielded radio-labeled translation products across a wide range of molecular weights, pointing to general, neuron-wide ERK-dependent translational modulation.

How might this ERK-dependent translational regulation correlate with the phenotype exhibited by dnMEK1 mice? Using metabolic pulse labeling and a pattern of repeated tetanic stimulations, Kelleher and colleagues tried to induce L-LTP in CA1 regions of control and mutant hippocampal slices, plus CA3 as internal control. Control slices showed increased translation in both CA1 and CA3. In the mutant slices, the same stimulation triggered increased translation only in CA3, but not CA1, possibly because there, the mutation abolished phosphorylation of ERK and translation initiation factors. They also saw increases in specific phosphorylation of ERK, S6, and eIF4E after fear conditioning in control slices; these increases were significantly reduced in mutant slices. Assessing all the evidence, the authors assert that ERK signaling regulates the translation necessary for long-lasting synaptic plasticity in the adult hippocampus.—Erene Mina

Erene Mina is a graduate student at the University of California, Irvine.


  1. ERK activation has been associated with the regulation of three major features of relevance to Alzheimer’s disease; these are hyperphosphorylation of tau (p-tau); memory and learning processes; and neurodegeneration. MEK1 is the upstream activator of ERK, and MEK inhibitors have been shown to prevent fibrillar Aβ-induced p-tau and neurodegeneration in hippocampal neurons (Rapoport and Ferreira, 2000). In postmortem brain tissue from Alzheimer’s disease patients, levels of phospho MEK1 have been demonstrated to be increased (Zhu et al., 2003), and furthermore, they were associated with pre-tangle neurons—a process that may precede Aβ deposition (Pei et al., 2002). These latter results are relevant to the study by Oddo et al. showing that LTP deficits occur before plaque and tangle pathology in a triple-transgenic model of Alzheimer’s disease (Oddo et al., 2003). However, the correlation between MEK1 and LTP has not been studied in in-vivo models for Alzheimer’s disease. Perhaps it would be possible, and certainly relevant, to extend the triple-transgenic mice model to a quadruple-transgenic, by further expressing a dominant negative MEK1? I leave the answer to specialists.

    The merit of this study by Kelleher and colleagues is in the use of a model in which basal levels of active ERK are preserved. In this same study, the conditional inhibition of ERK leads to selective impairment of the phosphorylation of ribosomal protein S6, eIF4E, and 4EBP1, which play key roles in translational regulation necessary to LTP and long-term memory. The activity of eIF4E can be regulated by 4EBP1 and is influenced through many signaling pathways including PI3K and Ras, viral infections, and cellular stresses. It is noteworthy to mention two other factors—insulin and BDNF—suggested to be associated to Alzheimer’s disease; these also influence eIF4E. Insulin induces the phosphorylation of 4EBP1 and its dissociation from eIF4E (Gingras, 1999). Increasing evidence indicates that BDNF plays a key role in memory and learning. In addition, polymorphism in BDNF has been associated with Alzheimer’s disease (Riemenschneider et al., 2002). The cellular distribution of eIF4E is regulated by BDNF, a regulation that may involve integrins known to be involved in certain forms of synaptic plasticity (Smart et al., 2003).

    In light of these results, further studies are needed to clarify the role of the MEK1 and the downstream translational regulators in learning and memory, and in the other neurodegenerative processes involved in Alzheimer’s disease.


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Paper Citations

  1. . Distribution, levels, and activation of MEK1 in Alzheimer's disease. J Neurochem. 2003 Jul;86(1):136-42. PubMed.

Further Reading

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Primary Papers

  1. . Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell. 2004 Feb 6;116(3):467-79. PubMed.