Multiple components of eIF4F are required for protein synthesis-dependent hippocampal long-term potentiation.
Persistent forms of synaptic plasticity are widely thought to require the synthesis of new proteins. This feature of long-lasting forms of plasticity largely has been demonstrated using inhibitors of general protein synthesis, such as either anisomycin or emetine. However, these drugs, which inhibit elongation, cannot address detailed questions about the regulation of translation initiation, where the majority of translational control occurs. Moreover, general protein synthesis inhibitors cannot distinguish between cap-dependent and cap-independent modes of translation initiation. In the present study, we took advantage of two novel compounds, 4EGI-1 and hippuristanol, each of which targets a different component of the eukaryotic initiation factor (eIF)4F initiation complex, and investigated their effects on long-term potentiation (LTP) at CA3-CA1 synapses in the hippocampus. We found that 4EGI-1 and hippuristanol both attenuated long-lasting late-phase LTP induced by two different stimulation paradigms. We also found that 4EGI-1 and hippuristanol each were capable of blocking the expression of newly synthesized proteins immediately after the induction of late-phase LTP. These new pharmacological tools allow for a more precise dissection of the role played by translational control pathways in synaptic plasticity and demonstrate the importance of multiple aspects of eIF4F in processes underlying hippocampal LTP, laying the foundation for future studies investigating the role of eIF4F in hippocampus-dependent memory processes.
Department of Physiology and Neuroscience, Langone Medical Center and School of Medicine, New York University, New York, New York 10012, USA.
Charles A
CA
Hoeffer
Emanuela
E
Santini
Tao
T
Ma
Elizabeth C
EC
Arnold
Ashley M
AM
Whelan
Helen
H
Wong
Philippe
P
Pierre
Jerry
J
Pelletier
Eric
E
Klann
D000818:Animals; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006835:Hydrazones; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009574:Nitro Compounds / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013261:Sterols / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology
C517852:4EGI-1 compound; D039562:Eukaryotic Initiation Factor-4F; D006835:Hydrazones; D009574:Nitro Compounds; D011500:Protein Synthesis Inhibitors; D013261:Sterols; D013844:Thiazoles; C510125:hippuristanol