Translational Control Of Learning and Memory
Mechanisms of translational control in synaptic plasticity and cognitive function
It has been known for many years that long-lasting forms of synaptic plasticity and long-term memory require new protein synthesis. However, until the early 2000s, little was known concerning the signaling pathways required to couple activation of various neurotransmitter receptors to the translation machinery during these processes. Our laboratory has spent many years delineating the regulation of translation initiation by the mTORC1 and ERK signaling cascades during LTP, LTD, and memory formation in the hippocampus. In particular, using molecular, biochemical, electrophysiological, and behavioral approaches we found that proper regulation of the mTORC1 substrates 4E-BP2/eIF4E and p70 S6 kinase (S6K1), as well as the regulation of eIF2α by the kinase PERK are critical for multiple types of protein synthesis-dependent long-lasting synaptic plasticity and long-term memory. We continue to focus our efforts on understanding the distinct roles of the various types of translational control in long-lasting synaptic plasticity and memory using pharmacological and genetic approaches in various brain regions, including the hippocampus, amygdala, and prefrontal cortex.
Selected important publications since 2014:
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. PMCID: PMC2630531
Trinh, M.A., Kaphzan, H., Wek, R.C., Pierre, P., Cavener, D.R., and Klann, E. (2012) Brain-specific disruption of the eIF2α kinase PERK decreases ATF4 expression and impairs behavioral flexibility. Cell Rep. 1: 676- 688. PMCID: PMC3401382
Huynh, T.N., Santini, E., and Klann, E. (2014) Requirment of mammaliant target of rapamycin complex 1 downstream effectors in cued fear memory reconsolidation and its persistence. J. Neurosci. 34: 9034- 9039. PMCID: PMC4078080.
Huynh, T., Santini, E., Mojica, E., Fink, A.E., Hall, B.S., Fetcho, R.N., Grosenick, L., Deisseroth, K.,
LeDoux, J.E., Liston, C., and Klann, E. (2017) Activation of a novel p70 S6 kinase 1-dependent signaling cascade in the basal nucleus of the amygdala is required for the acquisition of extinction memory.
Mol. Psychiatry, in press. PMCID: in progress