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The Journal of Neuroscience, May 30, 2007, 27(22):5885-5894; doi:10.1523/JNEUROSCI.4548-06.2007
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Cellular/Molecular
Mitogen-Activated Protein Kinase Upregulates the Dendritic Translation Machinery in Long-Term Potentiation by Controlling the Mammalian Target of Rapamycin Pathway
Panayiotis Tsokas,1 * Tao Ma,1 * Ravi Iyengar,1 Emmanuel M. Landau,1,2,3 andRobert D. Blitzer1,2 Departments of 1Pharmacology and Biological Chemistry and 2Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, and 3Psychiatry Service, Bronx Veterans Administration Medical Center, Bronx, New York 10463
Correspondence should be addressed to Robert D. Blitzer, Department of Pharmacology and Biological Chemistry, Box 1215, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029. Email: robert.blitzer{at}mssm.edu
Protein synthesis is required for persistent forms of synaptic plasticity, including long-term potentiation (LTP). A key regulator of LTP-related protein synthesis is mammalian target of rapamycin (mTOR), which is thought to modulate translational capacity by facilitating the synthesis of particular components of the protein synthesis machinery. Recently, extracellularly regulated kinase (ERK) also was shown to mediate plasticity-related translation, an effect that may involve regulation of the mTOR pathway. We studied the interaction between the mTOR and ERK pathways in hippocampal LTP induced at CA3–CA1 synapses by high-frequency synaptic stimulation (HFS). Within minutes after HFS, the expression of multiple translational proteins, the synthesis of which is under the control of mTOR, increased in area CA1 stratum radiatum. This upregulation was detected in pyramidal cell dendrites and was blocked by inhibitors of the ERK pathway. In addition, ERK mediated the stimulation of mTOR by HFS. The possibility that ERK regulates mTOR by acting at a component further upstream in the phosphatidylinositide 3-kinase (PI3K)–mTOR pathway was tested by probing the phosphorylation of p90-S6 kinase, phosphoinositide-dependent kinase 1 (PDK1), and Akt. ERK inhibitors blocked HFS-induced phosphorylation of all three proteins at sites implicated in the regulation of mTOR. Moreover, a component of basal and HFS-induced ERK activity depended on PI3K, indicating that mTOR-mediated protein synthesis in LTP requires coincident and mutually dependent activity in the PI3K and ERK pathways. The role of ERK in regulating PDK1 and Akt, with their extensive effects on cellular function, has important implications for the coordinated response of the neuron to LTP-inducing stimulation.
Key words: mammalian target of rapamycin; mitogen-activated protein kinase; dendrites; ERK; hippocampus; LTP; protein synthesis; synaptic plasticity
Received Oct. 19, 2006; revised April 20, 2007; accepted April 25, 2007.
Correspondence should be addressed to Robert D. Blitzer, Department of Pharmacology and Biological Chemistry, Box 1215, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029. Email: robert.blitzer{at}mssm.edu
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