Genetic removal of eIF 2α kinase PERK in mice enables hippocampal L‐ LTP independent of mTORC 1 activity

• Published in: Journal of neurochemistry Vol. 146; no. 2; pp. 133 - 144
• Main Authors: Zimmermann, Helena R., Yang, Wenzhong, Beckelman, Brenna C., Kasica, Nicole P., Zhou, Xueyan, Galli, Lucas Dufresne, Ryazanov, Alexey G., Ma, Tao
• Format: Journal Article
• Language: English
• Published: 01.07.2018
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14306

Abstract Characterization of the molecular signaling pathways underlying protein synthesis‐dependent forms of synaptic plasticity, such as late long‐term potentiation (L‐ LTP ), can provide insights not only into memory expression/maintenance under physiological conditions but also potential mechanisms associated with the pathogenesis of memory disorders. Here, we report in mice that L‐ LTP failure induced by the mammalian (mechanistic) target of rapamycin complex 1 ( mTORC 1) inhibitor rapamycin is reversed by brain‐specific genetic deletion of PKR ‐like ER kinase, PERK ( PERK KO ), a kinase for eukaryotic initiation factor 2α ( eIF 2α). In contrast, genetic removal of general control non‐derepressible‐2, GCN 2 ( GCN 2 KO ), another eIF 2α kinase, or treatment of hippocampal slices with the PERK inhibitor GSK 2606414, does not rescue rapamycin‐induced L‐ LTP failure, suggesting mechanisms independent of eIF 2α phosphorylation. Moreover, we demonstrate that phosphorylation of eukaryotic elongation factor 2 ( eEF 2) is significantly decreased in PERK KO mice but unaltered in GCN 2 KO mice or slices treated with the PERK inhibitor. Reduction in eEF 2 phosphorylation results in increased general protein synthesis, and thus could contribute to the mTORC 1‐independent L‐ LTP in PERK KO mice. We further performed experiments on mutant mice with genetic removal of eEF 2K ( eEF 2K KO ), the only known kinase for eEF 2, and found that L‐ LTP in eEF 2K KO mice is insensitive to rapamycin. These data, for the first time, connect reduction in PERK activity with the regulation of translation elongation in enabling L‐ LTP independent of mTORC 1. Thus, our findings indicate previously unrecognized levels of complexity in the regulation of protein synthesis‐dependent synaptic plasticity. image Read the Editorial Highlight for this article on page 119 . Cover Image for this issue: doi: 10.1111/jnc.14185 .