eIF2α phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory
eIF2α phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory
复制标题
DOI：
10.1016/j.cell.2007.01.050
复制
发表时间：
2007-04-06
期刊：
影响因子：
64.5
通讯作者：
Sonenberg, Nahum
中科院分区：
文献类型：
--
作者：
Costa-Mattioli, Mauro;Gobert, Delphine;Sonenberg, Nahum
长时程增强(LTP)和记忆(LTM)的晚期需要新的基因表达，但这些过程背后的分子机制尚不完全清楚。EIF2α的磷酸化抑制一般翻译，但选择性地刺激ATF4的翻译，ATF4是CREB介导的晚期LTP(L-LTP)和LTM的抑制因子。我们使用药物遗传学的双向方法来检测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磷酸化水平降低，海马片中诱发L-LTP的阈值降低，记忆能力增强。相反，当通过向海马区注入阻止eIF2α去磷酸化的小分子Sal003而增加eIF2α的磷酸化时，只有早期LTP被反复强直刺激诱发，LTM受到损害。这些发现强调了eIF2α中单个磷酸化位点作为L-LTP和LTM形成的关键调节因子的重要性。
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 eIF2 alpha 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 eIF2 alpha phosphorylation in synaptic plasticity and behavioral learning. We show that in eIF2 alpha(+/S51A) mice, in which eIF2 alpha 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 eIF2 alpha phosphorylation is increased by injecting into the hippocampus a small molecule, Sal003, which prevents the dephosphorylation of eIF2 alpha. These findings highlight the importance of a single phosphorylation site in eIF2 alpha as a key regulator of L-LTP and LTM formation.