https://www.ncbi.nlm.nih.gov/pubmed/28484273
Swiatkowski P1,2, Nikolaeva I1,2, Kumar G1, Zucco A1,3, Akum BF1, Patel MV1,3, D'Arcangelo G1, Firestein BL4.
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 mTORC1, 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.
- PMID:
- 28484273
- PMCID:
- PMC5431483
- DOI:
- 10.1038/s41598-017-01826-w
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