Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress

Abstract

The activity of the mammalian target of rapamycin (mTOR), an ubiquitously expressed serine/threonine kinase, is central to the regulation of translation initiation and, consequently protein synthesis required for long-term potentiation and new synaptic connections. Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine. Our prior work documented the first evidence of robust deficits in the mTOR signaling pathway in the prefrontal cortex (PFC) from subjects diagnosed with major depressive disorder (MDD). The goal of this study was to determine whether alterations in mTOR signaling can be observed in rats exposed to the chronic unpredictable stress (CUS) model of depression. In the present study, we examined the effect of CUS on the expression of phosphorylated mTOR and its downstream signaling components in the frontal cortex, hippocampus, amygdala, and dorsal raphe. We also examined the effect of CUS on the expression of kinases that phosphorylate mTOR such as extracellular signal-regulated kinase (ERK1/2) and protein kinase B/Akt (Akt1). In addition, we examined the effect of stress on the phosphorylation of GluR1 an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit. We found that eight-weeks of CUS exposure significantly decreased the phosphorylation levels of mTOR and its downstream signaling components in the amygdala. Reduced level of phospho-mTOR in the amygdala was accompanied by decreased phosphorylation of ERK-1/2, Akt-1, and GluR1. No significant changes were seen in the frontal cortex, hippocampus, or dorsal raphe. Our study demonstrates that long-term stress exposure results in brain region-specific abnormalities in signaling pathways previously linked to novel mechanisms for rapid antidepressant effects. These observations are in line with evidence showing that mTOR and its upstream and downstream signaling partners could be important targets for the development of novel antidepressants.

Ketamine ameliorates depressive-like behaviors and immune alterations in adult rats following maternal deprivation

“…In CSF, the two-way ANOVA did not show differences in TNF-␣ levels for ketamine treatment (F (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) (n = 5-6). *P < 0.05 vs. non-deprived + saline; # P < 0.05 vs. deprived rats treated with saline according to two-way ANOVA followed by Tukey post hoc test.…”

“…2B). The two-way ANOVA revealed differences in IL-6 levels for ketamine treatment (F (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) = 9288; p = 0.009; Fig. 2C) and for deprivation vs. ketamine treatment interaction (F (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) = 5065; p = 0.041; Fig.…”

“…The glutamatergic system is one such target of study in depression. This theory is supported by the fact that patients with depression exhibit elevated levels of glutamate in serum and brain tissue [8,9], and mainly because antagonists of N-methyl-d-aspartate (NMDA), such as ketamine, have been presenting antidepressant effects in animal models, as well as rapid onset in humans with depression [10][11][12][13][14].…”

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

“…[44][45][46] Interestingly, chronic stress and administration of ketamine were found to modulate the phosphorylation of GluA1 in the hippocampus 5,38 and amygdala. 47 We therefore examined the possibility that a potential mechanism for LTP induction by HFS and inhibition by ketamine involved an altered phosphorylation of GluA1 in the NAc. We performed western blotting experiments with slices from which the NAc was dissected and frozen, and we found that ketamine did not affect the total levels of GluA1 or Ser 831 -GluA1 phosphorylation.…”

Role of calcium, glutamate and NMDA in major depression and therapeutic application

“…Indeed, one of the pathways required for the NMDA actions is the mTOR signaling pathway. The mTOR signaling pathway is disturbed in the prefrontal cortex from subjects diagnosed with major depressive disorder (Chandran et al, 2013). Chronic unpredictable stress decreases the phosphorylation levels of mTOR and its downstream signaling components, i.e., ERK-1/2, Akt-1 and GluR1 (Chandran et al, 2013).…”