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首页> 美国卫生研究院文献>Scientific Reports >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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Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival

机译：独立于Akt的mTORC1和GSK3β信号传导在致死性NMDA损伤中的作用以及神经元电生理和存活的恢复

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摘要

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.
机译：N-甲基-D-天冬氨酸（NMDA）受体的过度刺激介导的谷氨酸诱导的兴奋性毒性是引起神经元继发性损伤的机制。损伤的早期阶段引起树突棘的丧失和突触活性的改变。雷帕霉素的磷脂酰肌醇-4,5-双磷酸3-激酶/ Akt /哺乳动物靶标（PI3K / Akt / mTOR）途径与突触强度，活性，成熟和轴突再生的调控有关。本研究的重点是在NMDA诱导的损伤之前，操纵Akt和几个下游靶标（例如GSK3β，FOXO1和mTORC1）后，神经元的生理和存活情况。我们的分析表明，暴露于亚致死水平的NMDA不会在受伤后两小时和二十四小时改变Akt，S6和GSK3β的磷酸化。电生理记录表明，NMDA诱导的损伤在两小时和二十四小时导致自发性兴奋性突触后突触电流显着降低，并且可以通过抑制mTORC1或GSK3β而不是Akt来防止这种表型。此外，抑制mTORC1或GSK3β可以促进NMDA诱导的损伤后神经元的存活。因此，NMDA诱导的兴奋性毒性涉及一种机制，该机制需要mTORC1和GSK3β的允许活性，这证明了这些激酶在神经元对损伤的反应中的重要性。

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