Tonegawa Lab Members
Memory Consolidation
A critical feature of both memory consolidation and the formation of long-lasting synaptic plasticity is a requirement for new mRNA and protein synthesis. Previous studies of memory consolidation have largely focused on the regulation of gene expression, establishing an important role for a transcription factor, the cyclic AMP–response element–binding protein (CREB), in this process. For instance, we previously generated transgenic mice in which a dominant-negative form of the Ca2+/calmodulin-dependent protein kinase IV (dn CaMKIV) inhibits endogenous Ca2+-stimulated CaMKIV activity in the postnatal forebrain. In these transgenic mice, an attenuation of a neural activity-induced CREB phosphorylation, a deficit in the protein synthesis–dependent long-term plasticity, and an impairment of the consolidation of long-term memory correlated well. These experiments identified the crucial role of neural activity-dependent CaMKIV signaling in the neuronal nucleus in memory consolidation.
In a more recent study, we examined a role of another kinase cascade involving ERK (extracellular signal-regulated kinase), which is activated in response to calcium influx and neurotrophin stimulation. Although previous studies relying on the use of pharmacologic inhibitors have implicated ERK activation in LTP and memory, the underlying cellular and molecular mechanisms remain unclear. We generated transgenic mice in which ERK activation is inhibited by a dominant-negative ERK kinase (dnMEK1) transgene only in the postnatal forebrain. Late LTP was impaired at Schaffer collateral (SC)-CA1 synapses, whereas early LTP, paired-pulse facilitation, and basal synaptic transmission were normal. The mutant mice also exhibited a selective impairment in long-term memory in contextual fear conditioning. We further investigated the role of the ERK-signaling pathway in activity-dependent protein synthesis by applying transfection techniques to cultured hippocampal neurons. The CaMKII 3'-UTR (untranslated region) has been implicated in translation regulation of the dendritically localized CaMKII mRNA in response to neuronal activity, but such a function has not been directly demonstrated and the second messenger pathways that might regulate such a process remain obscure. This was directly demonstrated by transfecting in vitro synthesized, capped EGFP (enhanced green fluorescent protein) mRNA (not DNA) carrying the CaMKII 3'-UTR sequences and testing the effect of cotransfection of the constitutively active MEK1 plasmid. Furthermore, translation of the reporter EGFP mRNA was strongly stimulated by treatment with brain-derived neurotrophic factor (BDNF) and strongly inhibited by treatment with the MEK inhibitor UO126. These data provide convincing evidence that the ERK-signaling pathway is an important regulator of activity-dependent translation in neurons. We propose that the ERK-signaling pathway governs memory consolidation and long-lasting synaptic plasticity, at least in part, through a novel role in the regulation of local protein synthesis in neurons.
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Tonegawa
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The Picower Center for Learning and Memory at MIT