Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of four known kinases that respond to cellular stress by deactivating the eukaryotic initiation factor 2 β (eIF2β) or other signal transduction cascades. Recently, both eIF2β and its kinases were found to play a role in normal and pathological brain function. Here, we show that reduction of either the amount or the activity of PERK, specifically in the CA1 region of the hippocampus in young adult male mice, enhances neuronal excitability and improves cognitive function. In addition, this manipulation rescues the age-dependent cellular phenotype of reduced excitability and memory decline. Specifically, the reduction of PERK expression in the CA1 region of the hippocampus of middle-aged male mice using a viral vector rejuvenates hippocampal function and improves hippocampal-dependent learning. These results delineate a mechanism for behavior and neuronal aging and position PERK as a promising therapeutic target for age-dependent brain malfunction.
Bibliographical noteFunding Information:
This work was supported by the Israeli Ministry of Science, Technology, and Space (MOST 3-12080 to K.R.); the Israel Science Foundation (ISF 1003/12, ISF-IDRC 2395/2015 to K.R.); the Wolfson Charitable Trust (K.R.); the Ministry of Science and Technology (Eshkol Postdoctoral Fellowship to H.O.-S.); the Tauber Foundation (Fellowship to H.O.-S.); and the Israeli Planning and Budgeting Committee Program Fellowships for Outstanding Post-Doctoral FellowsfromChinaandIndia(V.S.).WethankthemembersoftheK.R.laboratory,specificallyDr.ShunitGalBen-Ari, forcriticalreadingofthismanuscript;NoahCohenforvaluablecontributionstothismanuscript;andDr.AxtenJ.and G.S.K. for providing the PERK small-molecule inhibitor GSK2606414. The authors declare no competing financial interests. *V.S., H.O.-S., and D.C. contributed equally to this work.
© 2018 the authors.
- Intrinsic properties
- Memory enhancement
- Translation regulation
ASJC Scopus subject areas
- Neuroscience (all)