Costa-Mattioli Mauro, Gobert Delphine, Stern Elad, Gamache Karine, Colina Rodney, Cuello Claudio, Sossin Wayne, Kaufman Randal, Pelletier Jerry, Rosenblum Kobi, Krnjević Kresimir, Lacaille Jean-Claude, Nader Karim, Sonenberg Nahum
Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada.
Cell. 2007 Apr 6;129(1):195-206. doi: 10.1016/j.cell.2007.01.050.
The late phase of long-term potentiation (LTP) and memory (LTM) requires new gene expression, but the molecular mechanisms that underlie these processes are not fully understood. Phosphorylation of eIF2alpha inhibits general translation but selectively stimulates translation of ATF4, a repressor of CREB-mediated late-LTP (L-LTP) and LTM. We used a pharmacogenetic bidirectional approach to examine the role of eIF2alpha phosphorylation in synaptic plasticity and behavioral learning. We show that in eIF2alpha(+/S51A) mice, in which eIF2alpha phosphorylation is reduced, the threshold for eliciting L-LTP in hippocampal slices is lowered, and memory is enhanced. In contrast, only early-LTP is evoked by repeated tetanic stimulation and LTM is impaired, when eIF2alpha phosphorylation is increased by injecting into the hippocampus a small molecule, Sal003, which prevents the dephosphorylation of eIF2alpha. These findings highlight the importance of a single phosphorylation site in eIF2alpha as a key regulator of L-LTP and LTM formation.
长期增强（LTP）和记忆（LTM）的晚期阶段需要新的基因表达，但其潜在的分子机制尚未完全明确。真核生物翻译起始因子2α（eIF2α）的磷酸化会抑制整体翻译，但会选择性地刺激活化转录因子4（ATF4）的翻译，ATF4是一种能抑制cAMP反应元件结合蛋白（CREB）介导的晚期LTP（L-LTP）和LTM的蛋白。我们采用药物遗传学双向方法来研究eIF2α磷酸化在突触可塑性和行为学习中的作用。我们发现，在eIF2α（+/S51A）小鼠中，eIF2α的磷酸化减少，诱发海马切片中L-LTP的阈值降低，记忆增强。相反，当通过向海马体注射一种小分子Sal003来增加eIF2α的磷酸化时（Sal003可阻止eIF2α的去磷酸化），重复强直刺激仅诱发早期LTP，且LTM受损。这些发现突出了eIF2α中单个磷酸化位点作为L-LTP和LTM形成关键调节因子的重要性。
