Ribosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior

Abstract

Current treatments for major depressive disorder (MDD) have a time lag and are ineffective for a large number of patients. Development of novel pharmacological therapies requires a comprehensive understanding of the molecular events that contribute to MDD pathophysiology. Recent evidence points toward aberrant activity of synaptic proteins as a critical contributing factor. In the present studies, we used viral-mediated gene transfer to target a key mediator of activity-dependent synaptic protein synthesis downstream of mechanistic target of rapamycin complex 1 (mTORC1) known as p70 S6 kinase 1 (S6K1). Targeted delivery of two mutants of S6K1, constitutively active or dominant-negative, to the medial prefrontal cortex (mPFC) of rats allowed control of the mTORC1/S6K1 translational pathway. Our results demonstrate that increased expression of S6K1 in the mPFC produces antidepressant effects in the forced swim test without altering locomotor activity. Moreover, expression of active S6K1 in the mPFC blocked the anhedonia caused by chronic stress, resulting in a state of stress resilience. This antidepressant response was associated with increased neuronal complexity caused by enhanced S6K1 activity. Conversely, expression of dominant-negative S6K1 in the mPFC resulted in prodepressive behavior in the forced swim test and was sufficient to cause anhedonia in the absence of chronic stress exposure. Together, these data demonstrate a critical role for S6K1 activity in depressive behaviors, and suggest that pathways downstream of mTORC1 may underlie the pathophysiology and treatment of MDD.M ajor depressive disorder (MDD) affects nearly one-fifth of the US population (1) and represents the second-leading cause of disability worldwide. Despite its prevalence, successful treatment of MDD is hindered by a lack of understanding of the molecular mechanisms underlying the disorder. Recent evidence points to a critical role for the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, which controls synaptic protein synthesis in mediating antidepressant behavior.Drugs that demonstrate rapid antidepressant activity in preclinical models of depression, such as the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, the NR2B-selective antagonist Ro 25-6981, the muscarinic antagonist scopolamine, and the metabotropic glutamate receptor 2/3 (mGluR2/3) antagonist LY341495, all share a common signaling profile through cellular protein synthesis cascades. All of these drugs increase activity of mTORC1 and its downstream substrates p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1) (2-4). Pharmacological inhibition of mTORC1 in the medial prefrontal cortex (mPFC) of rats completely blocks the behavioral effects of these drugs (2-4). These data suggest that enhanced signaling through the mTORC1 pathway is required for rapid antidepressant responses. It remains unknown, however, whether direct modulation of this translational pathway is sufficient to control depressive behavior, a...

The critical role of quercetin in autophagy and apoptosis in HeLa cells

“…Each bar represents the mean±SD of three independent experiments; *p<0.001, compared with control, one-way ANOVA or Student-Newman-Keuls Phosphorylation activation of downstream substrates is the major activation of mTORC1 signaling pathway. Ribosomal protein S6 kinase 1 (S6K1) is a key substrate for the activation of the phosphorylation levels of mTORC1 signaling pathway [13]. In order to investigate whether mTORC 1 pathway is involved in the regulation of autophagy in HeLa cells induced by quercetin, Western blot was used to detect the phosphorylated protein expression levels of S6K1 (p-S6K1) and S6KI in HeLa cells.…”

Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures

“…For dendritic morphology, 0.4 million cells per 6-well were plated on coverslips. On DIV 3, cells were incubated with an AAV2 viral vector that expresses green fluorescence protein (AAV2-GFP) as previously described (Dwyer et al, 2015) for 72 hr. Following viral incubation, media was changed and cells were treated with ketamine (500 nM), LY 341495 (10 nM), or GLYX-13 (3nM) at DIV 17 and then fixed 24hr after with 4% PFA.…”

Emerging treatment mechanisms for depression: focus on glutamate and synaptic plasticity

“…Ketamine administration rapidly increases phosphorylation of mTORC1 signaling proteins in the PFC and the behavioral effects of ketamine are blocked by pretreatment of the selective mTORC1 inhibitor rapamycin, providing further support for the role of mTORC1 in the rapid-acting antidepressant effects of ketamine [9, 55] (Figure 1). In addition, a recent study has demonstrated that expression of signaling proteins that increase or decrease mTORC1 signaling in the medial PFC produce antidepressant or pro-depressive actions, respectively [29, 56]. …”