Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival

Abstract Glutamate-induced excitotoxicity, mediated by overstimulation of N-methyl-D-aspartate (NMDA) receptors, is a mechanism that causes secondary damage to neurons. The early phase of injury causes loss of dendritic spines and changes to synaptic activity. The phosphatidylinositol-4,5-bisphospha...

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Autores principales:	Przemyslaw Swiatkowski, Ina Nikolaeva, Gaurav Kumar, Avery Zucco, Barbara F. Akum, Mihir V. Patel, Gabriella D’Arcangelo, Bonnie L. Firestein
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/187734828ebb47e29e21b6060cf27c55
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spelling	oai:doaj.org-article:187734828ebb47e29e21b6060cf27c552021-12-02T11:52:58ZRole of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival10.1038/s41598-017-01826-w2045-2322https://doaj.org/article/187734828ebb47e29e21b6060cf27c552017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01826-whttps://doaj.org/toc/2045-2322Abstract Glutamate-induced excitotoxicity, mediated by overstimulation of N-methyl-D-aspartate (NMDA) receptors, is a mechanism that causes secondary damage to neurons. The early phase of injury causes loss of dendritic spines and changes to synaptic activity. The phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt/ mammalian target of rapamycin (PI3K/Akt/mTOR) pathway has been implicated in the modulation and regulation of synaptic strength, activity, maturation, and axonal regeneration. The present study focuses on the physiology and survival of neurons following manipulation of Akt and several downstream targets, such as GSK3β, FOXO1, and mTORC1, prior to NMDA-induced injury. Our analysis reveals that exposure to sublethal levels of NMDA does not alter phosphorylation of Akt, S6, and GSK3β at two and twenty four hours following injury. Electrophysiological recordings show that NMDA-induced injury causes a significant decrease in spontaneous excitatory postsynaptic currents at both two and twenty four hours, and this phenotype can be prevented by inhibiting mTORC1 or GSK3β, but not Akt. Additionally, inhibition of mTORC1 or GSK3β promotes neuronal survival following NMDA-induced injury. Thus, NMDA-induced excitotoxicity involves a mechanism that requires the permissive activity of mTORC1 and GSK3β, demonstrating the importance of these kinases in the neuronal response to injury.Przemyslaw SwiatkowskiIna NikolaevaGaurav KumarAvery ZuccoBarbara F. AkumMihir V. PatelGabriella D’ArcangeloBonnie L. FiresteinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Przemyslaw Swiatkowski Ina Nikolaeva Gaurav Kumar Avery Zucco Barbara F. Akum Mihir V. Patel Gabriella D’Arcangelo Bonnie L. Firestein Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival
description	Abstract Glutamate-induced excitotoxicity, mediated by overstimulation of N-methyl-D-aspartate (NMDA) receptors, is a mechanism that causes secondary damage to neurons. The early phase of injury causes loss of dendritic spines and changes to synaptic activity. The phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt/ mammalian target of rapamycin (PI3K/Akt/mTOR) pathway has been implicated in the modulation and regulation of synaptic strength, activity, maturation, and axonal regeneration. The present study focuses on the physiology and survival of neurons following manipulation of Akt and several downstream targets, such as GSK3β, FOXO1, and mTORC1, prior to NMDA-induced injury. Our analysis reveals that exposure to sublethal levels of NMDA does not alter phosphorylation of Akt, S6, and GSK3β at two and twenty four hours following injury. Electrophysiological recordings show that NMDA-induced injury causes a significant decrease in spontaneous excitatory postsynaptic currents at both two and twenty four hours, and this phenotype can be prevented by inhibiting mTORC1 or GSK3β, but not Akt. Additionally, inhibition of mTORC1 or GSK3β promotes neuronal survival following NMDA-induced injury. Thus, NMDA-induced excitotoxicity involves a mechanism that requires the permissive activity of mTORC1 and GSK3β, demonstrating the importance of these kinases in the neuronal response to injury.
format	article
author	Przemyslaw Swiatkowski Ina Nikolaeva Gaurav Kumar Avery Zucco Barbara F. Akum Mihir V. Patel Gabriella D’Arcangelo Bonnie L. Firestein
author_facet	Przemyslaw Swiatkowski Ina Nikolaeva Gaurav Kumar Avery Zucco Barbara F. Akum Mihir V. Patel Gabriella D’Arcangelo Bonnie L. Firestein
author_sort	Przemyslaw Swiatkowski
title	Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival
title_short	Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival
title_full	Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival
title_fullStr	Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival
title_full_unstemmed	Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival
title_sort	role of akt-independent mtorc1 and gsk3β signaling in sublethal nmda-induced injury and the recovery of neuronal electrophysiology and survival
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/187734828ebb47e29e21b6060cf27c55
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Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival

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