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-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.

Reciprocal regulation of miR-214 and PTEN by high glucose regulates renal glomerular mesangial and proximal tubular epithelial cell hypertrophy and matrix expansion

“…8, C and D). Akt-independent activation of mTORC1 is known (79,81). However, expression of constitutively active Myr Akt reversed the attenuation of S6 kinase phosphorylation induced by anti-miR-214 ( Fig.…”

SK Channel Modulates Synaptic Plasticity by Tuning CaMKIIα/β Dynamics

“…In synaptic potentiation, high-frequency spiking events involve the transient surge of postsynaptic Ca ++ current that is mediated by NMDAR-linked ionotropic neurotransmission (Xia et al, 1996; Coultrap and Bayer, 2012). In addition to the modulation of synaptic plasticity, the transient Ca ++ current also couples LTP to cellular regulation and gene expression (Xia et al, 1996; Li et al, 2001; Yao and Wu, 2001; Salter and Kalia, 2004; Yoshii and Constantine-Paton, 2007; Coultrap and Bayer, 2012; Stein et al, 2015; Takei et al, 2015; Sanderson et al, 2016; Wang et al, 2016; Swiatkowski et al, 2017). Ca ++ surge produced by NMDAR activates synaptic Ca ++ -Calmodulin-dependent kinase 2 (CaMKII) by facilitating autophosphorylation at T286/287 sites of the 9α/3β components of the holoenzyme.…”

Influence of Phosphatidylinositol-3-Kinase/Protein Kinase B-Mammalian Target of Rapamycin Signaling Pathway on the Neuropathic Pain Complicated by Nucleoside Reverse Transcriptase Inhibitors for the Treatment of HIV Infection

“…Recent study has shown that rapamycin, a tool for the study of the Akt/mTOR signaling pathway, can effectively reduce the mechanical sensitivity of rats with chronic inflammatory pain. [ 26 ] After pretreatment with rapamycin, the late maintenance of long-term potentiation and long-term memory formation in the hippocampus were blocked, and the hyperalgesia induced by formalin was reduced; moreover, the excitability of spinal dorsal horn neurons was also significantly decreased. [ 27 28 ] To better understand, the effect of rapamycin on neuropathic pain, we applied rapamycin to stavudine-treated mice to further explore the role of rapamycin in hyperthermia and mechanical pain abnormalities.…”