Translational Control of Learning and Memory

It is well known that long-lasting forms of synaptic plasticity and memory require new protein synthesis. However, until recently, little was known concerning the signaling pathways required to couple activation of various neurotransmitter receptors to the translation machinery during these processes. Klann lab has spent many years delineating the regulation of cap-dependent translation initiation by the mTORC1 and ERK signaling cascades during long-term potentiation (LTP), long-term depression (LTD), and memory formation in the hippocampus. In particular, using molecular, biochemical, electrophysiological, and behavioral approaches we have found that proper regulation of the mTORC1 substrates 4E-BP2 and p70 S6 kinase (S6K1) are critical for multiple types of protein synthesis-dependent LTP, LTD, and long-term memory. We currently are focusing our efforts on understanding the distinct roles of the downstream effectors of mTORC1 on various types of memory using pharmacological and genetic approaches in various brain regions, including the hippocampus, amygdala, and prefrontal cortex. For recent selected examples of our work on this topic, please see: Hoeffer, C.A., Cowansage, K.K., Arnold, E.C., Banko, J.L., Moerke, N.J., Rodriguez, R., Schmidt, E.K., Klosi, E., Chorev, M., Lloyd, R.E., Pierre, P., Wagner, G., LeDoux, J.E., and Klann, E. (2011) Inhibition of the interactions between translation initiation factors eIF4E and eIF4G impairs long- term associative memory consolidation but not reconsolidation. Proc. Natl. Acad. Sci. USA 108: 3383-3388. Monfils, M.H., Cowansage, K.K., Klann, E., and LeDoux, J.E. (2009) Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science 324: 951-955. Hoeffer, C.A., Tang, W., Wong, H., Santillan, A., Patterson, R.J., Martinez, L.A., Tejada-Simon, M.V., Paylor, R., Hamilton, S.L., and Klann, E. (2008) Removal of FKBP12 enhances mTOR/Raptor interactions, LTP, memory, and perseverative/repetitive behavior. Neuron 60: 832-845. Antion, M.D., Hou, L., Wong, H., Hoeffer, C.A., and Klann, E. (2008) mGluR-dependent long-term depression is associated with increased phosphorylation of S6 and synthesis of EF1A, but remains expressed in S6K-deficient mice. Mol. Cell. Biol. 28: 2996-3007. Antion, M.D., Merhav, M., Hoeffer, C.A., Reis, G., Kozma, S.C., Thomas, G., Schuman, E.M., Rosenblum, K., and Klann, E. (2008) Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity. Learn. Mem. 15: 29-38.