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Summary: Nahum Sonenberg’s primary research interest has been to understand the importance of the control of protein synthesis in biology and medicine. He investigates the importance of translational control in cancer, obesity, innate immunity, and learning and memory. He has also had a long-term interest in virology—studying poliovirus, rhinoviruses, and HIV. HHMI is currently funding his research on learning and memory.

Eukaryotic cellular mRNAs contain a cap structure (m⁷GpppN) at their 5′ terminus, which facilitates 40S ribosome binding to the mRNA. Cap function is mediated by the initiation factor eIF4F, which consists of three subunits: eIF4E, the cap-binding polypeptide; eIF4A, an RNA helicase; and eIF4G, which forms a platform for the binding of eIF4A and eIF4E and bridges the mRNA with the ribosome. We discovered a family of 4E-binding proteins (4E-BPs), whose members sequester eIF4E, thus preventing eIF4E-eIF4G interaction and eIF4F assembly. The activity of 4E-BPs is modulated by phosphorylation. A critical signaling pathway that controls translation rates via 4E-BP phosphorylation is the PI3K/Akt/mTOR pathway. Studies on learning and a variety of forms of synaptic plasticity have revealed a link between translation and learning and memory. Interestingly, the PI3K/Akt/ mTOR pathway has been implicated in synaptic plasticity and memory. However, the molecular mechanisms by which translation regulates synaptic plasticity and memory are poorly understood. To explore the role of translation initiation in hippocampal long-term potentiation (LTP) and learning and memory, the laboratory generated knockout mice for 4E-BP2, which is the predominant 4E-BP isoform in the brain. 4E-BP2 KO mice are impaired in hippocampus-dependent learning and memory tasks. Furthermore, 4E-BP2 KO mice exhibit a lowered threshold for elicitation of LTP, inasmuch as one train of 100 Hz induced a strong and sustained LTP. This sustained LTP was dependent on transcription and translation. However, in brain slices from 4E-BP2 KO mice, L-LTP induced electrically with four trains of 100 Hz was impaired, which parallels the impaired spatial learning. These results suggest a critical role for proper regulation of the eIF4F complex and translation initiation by 4E-BP2 during LTP and learning and memory in the mouse hippocampus.

A second translational control mechanism of synaptic plasticity and memory is mediated by the translation initiation factor eIF2. The eukaryotic initiator factor eIF2, which consists of three subunits (α, β, and γ), binds to the initiator Met-tRNA^MET and GTP to form a ternary complex. eIF2 then associates with the small ribosomal subunit in its GTP-bound form. Phosphorylation of eIF2 causes a decrease in general translation, but stimulates translation of a subset of mRNAs, which includes the transcription factor ATF4. In diverse phyla, ATF4 is a repressor of cAMP-responsive element binding protein (CREB)–mediated gene expression, which is required for L-LTP and long-term memory. The expression of ATF4 is regulated at the level of translation. Neuronal activity-dependent modulation of eIF2α phosphorylation is likely to be important for sustained changes in synaptic transmission inasmuch as induction of L-LTP in hippocampal slices, by either titanic stimulation or treatment with forskolin or BDNF, is correlated with decreased eIF2α phosphorylation. In mice lacking GCN2, the eIF2α kinase, the reduction in phosphorylated eIF2α is associated with altered synaptic plasticity and memory. Strikingly, we recently demonstrated that eIF2α heterozygous mutants (eIF2α^+/S51A), in which the phosphorylation site in eIF2α is mutated, L-LTP and long term memory formation is enhanced, as determined by several behavioral tasks. Moreover, a small molecule inhibitor of eIF2α phosphatases, Sa1003, blocks L-LTP and memory storage. These results demonstrate that eIF2α phosphorylation is a critical step in the formation of L-LTP and memory. Thus, we discovered a potential drug target for memory enhancement.

Last updated September 2008