ERK Signaling Translates to New Memories

Abstract

Memory consolidation and the enduring changes in synaptic function that may underlie long-lasting memories both depend on synthesis of new mRNA and protein. The mechanisms by which synaptic activity affects transcription have been intensively explored, whereas the route to translational regulation is poorly understood. Kelleher et al. used cultured neurons and a mouse mutant to explore the involvement of the extracellular signal-regulated kinase (ERK) mitogen-associated protein kinase (MAPK) signaling pathway--which has been implicated in synaptic plasticity, learning, and memory--in stimulus-dependent translation. In primary hippocampal neurons, pharmacological analysis indicated that stimulus-dependent activation of a translational reporter and pulse labeling of endogenous transcripts depended on ERK signaling, as did phosphorylation of ribosomal protein S6 and the translation factors eIF4E and 4E-BP1. Transgenic mice expressing a dominant-negative form of the ERK kinase MAPK-extracellular signal regulated kinase-1 (dnMEK1) in postnatal forebrain exhibited impaired spatial reference memory and long-term contextual fear conditioning. Although basal hippocampal synaptic transmission, short-term plastic changes, and an early phase of long-term potentiation (LTP) appeared normal, pharmacological and kinetic analysis of late LTP (L-LTP, which depends on protein synthesis) suggested a selective deficit in the translational component of this process. Hippocampal slices from dnMEK1 mice showed reduced ERK phosphorylation, incorporation of 35 S-methionine, and phosphorylation of translation factors in response to L-LTP-inducing tetanic stimuli. Similarly, hippocampi from dnMEK1 mice showed reduced phosphorylation of ERK and translation factors in response to fear conditioning. Thus regulation of translation through the MAPK signaling pathway appears to play a critical role in long-lasting memory and long-term changes in synaptic function. R. J. Kelleher III, A. Govindarajan, H.-Y. Jung, H. Kang, S. Tonegawa, Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116 , 467-479 (2004). [Online Journal]