| LeDoux Lab 2008 SfN Abstracts |
|---|
| Program#/Poster#: | 591.25/UU12 |
| Title: | Effects of small molecule inhibition on the interaction between initiation factors eIF4E and eIF4G following associative fear conditioning |
| Location: | Washington Convention Center: Hall A-C |
| Presentation Time: | Tuesday, Nov 18, 2008, 8:00 AM - 9:00 AM |
| Authors: | *C. HOEFFER1, K. K.
COWANSAGE1, E. C. ARNOLD1, J. E. LEDOUX1,
N. MOERKE2, G. WAGNER3, E. KLANN1; 1Ctr. Neural Sci., New York Univ., New York, NY; 2Longwood/Department of Systems Biol., 33Department of Biol. Chem. and Mol. Pharmacol., Harvard Med. Sch., Boston, MA |
| Abstract: | New protein synthesis is required for
long-lasting synaptic plasticity and long-term memory. Understanding the
regulation of translational initiation in neurons is vital to elucidating
the molecular mechanisms underlying synaptic plasticity and memory formation.
Numerous studies examining the role of translation in learning and memory
have utilized protein synthesis inhibitors such as anisomycin and cycloheximide.
These compounds inhibit translation by blocking peptidyl transferase activity.
However, they also inhibit DNA replication and monoamine synthesis. Importantly,
they disrupt the normal signaling of critical protein kinase signaling pathways
such as mitogen-activated protein kinases (MAPKs) and stress-activated protein
kinases (SAPKs). These non-specific effects limit the interpretation of
experiments when they are used to study the role of translation in synaptic
plasticity and memory. Assembly of the eIF4E (4E) and eIF4G (4G) into a multi-protein complex is critical to initiation of translation. The formation of the 4E/4G complex facilitates eIF4A RNA helicase activity and recruitment of capped 5’ end of mRNA to the 40S ribosomal subunit, and peptide elongation. A recently identified small molecule compound, 4EGI-1, selectively disrupts this important interaction, inhibiting cap dependent mRNA translation. Interestingly, 4EGI-1 more effectively blocks the translation of mRNAs that contain highly structured 5’ UTR structure. In order to overcome steric interference presented by complex 5’ secondary structure, these mRNAs are more dependent on activities of the 4E/4G complex for translation. We selectively applied 4EGI-1 to the lateral amygdala (LA) in rats and found that, similar to studies conducted in cell culture, this compound effectively disrupts normal 4E/4G interaction. Importantly, application of 4EGI-1 disrupted memory consolidation following a Pavlovian fear conditioning paradigm. Interestingly, 4EGI-1 applied to the LA following reactivation failed to block reconsolidation. This finding supports the notion that consolidation and reconsolidation require the translation of different populations of mRNAs. This idea is further supported by biochemical data showing that 4G/4E binding is enhanced following initial fear conditioning but not at a corresponding time point following reactivation. Because 4EGI-1 specifically targets the highly regulated assembly of the 4E/4G complex, this inhibitor may be of particular interest because it may provide a way to more selectively block the translation of specific mRNAs involved activity-dependent translation rather than general protein synthesis. |
| Support: | NIH Grant NS034007 |
| NIH Grant NS047384 | |
| NIH Grant CA68262 |