*E. KLANN1, C. A. HOEFFER, Jr1, K. K. COWANSAGE1, N. MOERKE2, G. WAGNER2, J. LEDOUX1;
1Ctr. for Neural Sci., New York Univ., New York, NY; 2Biol. Chem. and Mol. Pharmacol., Harvard Med. Sch., Boston, MA

New protein synthesis is required for the many long-lasting forms of synaptic plasticity and long-term memory. Understanding the regulation of translational initiation in neurons is vital to elucidating the regulation of protein synthesis during 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 binding the 60S ribosomal subunit blocking peptidyl transferase activity. However, they also inhibit other cellular processes such as 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 and eIF4G into a multi-protein complex is critical to initiation of translation. The formation of the eIF4E/eIF4G 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 eIF4E/eIF4G 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 eIF4E/eIF4G interaction. We are currently examining the effects of 4EGI-1 on associative memory following a Pavlovian fear conditioning paradigm. These studies will determine whether this new compound can be applied to studies aimed at addressing the role of translation in memory function. Moreover, because the inhibitor specifically targets the highly regulated assembly of the eIF4E/eIF4G complex, its use should avoid the confounding activities presented by protein synthesis inhibitors currently in use. Finally, 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 Contributed By: NIH Grant NS048037 (E.K.); NIH Grant CA68262 (G.W.)


Program No. 91.14/SS5
Poster presentation:Monday, Saturday, Nov 03, 2007, 2:00 PM - 3:00 PM
Location: San Diego Convention Center: Halls B-H