Local inhibition of PERK enhances memory and reverses age-related deterioration of cognitive and neuronal properties

Vijendra Sharma; Hadile Ounallah-Saad; Darpan Chakraborty; Mohammad Hleihil; Rapita Sood; Iliana Barrera; Efrat Edry; Sailendrakumar Kolatt Chandran; Shlomo Ben Tabou de Leon; Hanoch Kaphzan; Kobi Rosenblum

doi:10.1523/JNEUROSCI.0628-17.2017

Local inhibition of PERK enhances memory and reverses age-related deterioration of cognitive and neuronal properties

Vijendra Sharma
, Hadile Ounallah-Saad
, Darpan Chakraborty
, Mohammad Hleihil
, Rapita Sood
, Iliana Barrera
, Efrat Edry
, Sailendrakumar Kolatt Chandran
, Shlomo Ben Tabou de Leon
, Hanoch Kaphzan
, Kobi Rosenblum

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	648-658
Number of pages	11
Journal	Journal of Neuroscience
Volume	38
Issue number	3
DOIs	https://doi.org/10.1523/JNEUROSCI.0628-17.2017
State	Published - 17 Jan 2018

Bibliographical note

Funding 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.

Publisher Copyright:
© 2018 the authors.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Aging
Intrinsic properties
Memory enhancement
PERK
Translation regulation

ASJC Scopus subject areas

General Neuroscience

Access to Document

10.1523/JNEUROSCI.0628-17.2017

Cite this

Sharma, V., Ounallah-Saad, H., Chakraborty, D., Hleihil, M., Sood, R., Barrera, I., Edry, E., Chandran, S. K., de Leon, S. B. T., Kaphzan, H., & Rosenblum, K. (2018). Local inhibition of PERK enhances memory and reverses age-related deterioration of cognitive and neuronal properties. Journal of Neuroscience, 38(3), 648-658. https://doi.org/10.1523/JNEUROSCI.0628-17.2017

@article{5e1ce974ff1747eca28e89850df4d21c,

title = "Local inhibition of PERK enhances memory and reverses age-related deterioration of cognitive and neuronal properties",

abstract = "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.",

keywords = "Aging, Intrinsic properties, Memory enhancement, PERK, Translation regulation",

author = "Vijendra Sharma and Hadile Ounallah-Saad and Darpan Chakraborty and Mohammad Hleihil and Rapita Sood and Iliana Barrera and Efrat Edry and Chandran, \{Sailendrakumar Kolatt\} and \{de Leon\}, \{Shlomo Ben Tabou\} and Hanoch Kaphzan and Kobi Rosenblum",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2018 the authors.",

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doi = "10.1523/JNEUROSCI.0628-17.2017",

language = "English",

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T1 - Local inhibition of PERK enhances memory and reverses age-related deterioration of cognitive and neuronal properties

AU - Sharma, Vijendra

AU - Ounallah-Saad, Hadile

AU - Chakraborty, Darpan

AU - Hleihil, Mohammad

AU - Sood, Rapita

AU - Barrera, Iliana

AU - Edry, Efrat

AU - Chandran, Sailendrakumar Kolatt

AU - de Leon, Shlomo Ben Tabou

AU - Kaphzan, Hanoch

AU - Rosenblum, Kobi

N1 - Funding 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. Publisher Copyright: © 2018 the authors.

PY - 2018/1/17

Y1 - 2018/1/17

N2 - 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.

AB - 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.

KW - Aging

KW - Intrinsic properties

KW - Memory enhancement

KW - PERK

KW - Translation regulation

UR - https://www.scopus.com/pages/publications/85040835612

U2 - 10.1523/JNEUROSCI.0628-17.2017

DO - 10.1523/JNEUROSCI.0628-17.2017

M3 - Article

C2 - 29196323

AN - SCOPUS:85040835612

SN - 0270-6474

VL - 38

SP - 648

EP - 658

JO - Journal of Neuroscience

JF - Journal of Neuroscience

IS - 3

ER -

Local inhibition of PERK enhances memory and reverses age-related deterioration of cognitive and neuronal properties

Abstract

Bibliographical note

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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