Abstract
Protein synthesis underlying activity-dependent synaptic plasticity is controlled at the level of mRNA translation. We examined the dynamics and spatial regulation of two key translation factors, eukaryotic initiation factor 4E (eIF4E) and elongation factor-2 (eEF2), during long-term potentiation (LTP) induced by local infusion of brain-derived neurotrophic factor (BDNF) into the dentate gyrus of anesthetized rats. BDNF-induced LTP led to rapid, transient phosphorylation of eIF4E and eEF2, and enhanced expression of eIF4E protein in dentate gyrus homogenates. Infusion of the extracellular signal-regulated kinase (ERK) inhibitor U0126 blocked BDNF-LTP and modulation of the translation factor activity and expression. Quantitative immunohistochemical analysis revealed enhanced staining of phospho-eIF4E and total eIF4E in dentate granule cells. The in vitro synaptodendrosome preparation was used to isolate the synaptic effects of BDNF in the dentate gyrus. BDNF treatment of synaptodendrosomes elicited rapid, transient phosphorylation of eIF4E paralleled by enhanced expression of alpha-calcium/calmodulin-dependent protein kinase II. In contrast, BDNF had no effect on eEF2 phosphorylation state in synaptodendrosomes. The results demonstrate rapid ERK-dependent regulation of the initiation and elongation steps of protein synthesis during BDNF-LTP in vivo. Furthermore, the results suggest a compartment-specific regulation in which initiation is selectively enhanced by BDNF at synapses, while both initiation and elongation are modulated at non-synaptic sites.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain-Derived Neurotrophic Factor / metabolism*
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Brain-Derived Neurotrophic Factor / pharmacology
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / drug effects
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Compartmentation / physiology
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Dendrites / drug effects
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Dendrites / metabolism
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Dentate Gyrus / drug effects
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Dentate Gyrus / metabolism*
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Drug Administration Routes
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Enzyme Inhibitors / pharmacology
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Eukaryotic Initiation Factor-4E / genetics
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Eukaryotic Initiation Factor-4E / metabolism
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Eukaryotic Initiation Factors / genetics
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Eukaryotic Initiation Factors / metabolism*
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Immunohistochemistry
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Long-Term Potentiation / drug effects
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Long-Term Potentiation / genetics*
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Male
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Nerve Tissue Proteins / biosynthesis*
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Nerve Tissue Proteins / genetics
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Peptide Elongation Factor 2 / genetics
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Peptide Elongation Factor 2 / metabolism
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Peptides / metabolism
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Phosphorylation
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Presynaptic Terminals / drug effects
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Presynaptic Terminals / metabolism
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Protein Biosynthesis / genetics*
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Rats
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Rats, Sprague-Dawley
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology
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Synaptosomes / drug effects
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Synaptosomes / metabolism
Substances
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Brain-Derived Neurotrophic Factor
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Enzyme Inhibitors
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Eukaryotic Initiation Factor-4E
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Eukaryotic Initiation Factors
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Nerve Tissue Proteins
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Peptide Elongation Factor 2
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Peptides
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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Extracellular Signal-Regulated MAP Kinases