Novel translational control in Arc-dependent long term potentiation consolidation in vivo.
Regulation of translation factor activity plays a major role in protein synthesis-dependent forms of synaptic plasticity. We examined translational control across the critical period of Arc synthesis underlying consolidation of long term potentiation (LTP) in the dentate gyrus of intact, anesthetized rats. LTP induction by high frequency stimulation (HFS) evoked phosphorylation of the cap-binding protein eukaryotic initiation factor 4E (eIF4E) and dephosphorylation of eIF2alpha on a protracted time course matching the time-window of Arc translation. Local infusion of the ERK inhibitor U0126 inhibited LTP maintenance and Arc protein expression, blocked changes in eIF4E and eIF2alpha phosphorylation state, and prevented initiation complex (eIF4F) formation. Surprisingly, inhibition of the mTOR protein complex 1 (mTORC1) with rapamycin did not impair LTP maintenance or Arc synthesis nor did it inhibit eIF4F formation or phosphorylation of eIF4E. Rapamycin nonetheless blocked mTOR signaling to p70 S6 kinase and ribosomal protein S6 and inhibited synthesis of components of the translational machinery. Using immunohistochemistry and in situ hybridization, we show that Arc protein expression depends on dual, ERK-dependent transcription and translation. Arc translation is selectively blocked by pharmacological inhibition of mitogen-activated protein kinase-interacting kinase (MNK), the kinase coupling ERK to eIF4E phosphorylation. Furthermore, MNK signaling was required for eIF4F formation. These results support a dominant role for ERK-MNK signaling in control of translational initiation and Arc synthesis during LTP consolidation in the dentate gyrus. In contrast, mTORC1 signaling is activated but nonessential for Arc synthesis and LTP. The work, thus, identifies translational control mechanisms uniquely tuned to Arc-dependent LTP consolidation in live rats.
Panja
Debabrata
D
Department of Biomedicine and Bergen Mental Health Research Center, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
Dagyte
Girstaute
G
Bidinosti
Michael
M
Wibrand
Karin
K
Kristiansen
Ase-Marit
AM
Sonenberg
Nahum
N
Bramham
Clive R
CR
D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism; D015347:RNA Probes; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic
D002070:Butadienes; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D039561:Eukaryotic Initiation Factor-4E; D048049:Extracellular Signal-Regulated MAP Kinases; D009419:Nerve Tissue Proteins; D009570:Nitriles; D011494:Protein Kinases; D015347:RNA Probes; D016194:Receptors, N-Methyl-D-Aspartate; D058570:TOR Serine-Threonine Kinases; C113580:U 0126; C092069:activity regulated cytoskeletal-associated protein