Akt Mediates GSK-3β Phosphorylation in the Rat Prefrontal Cortex during the Process of Ketamine Exerting Rapid Antidepressant Actions

Abstract

Ketamine may produce rapid and sustained antidepressant effects. Despite the fact that the detailed underlying mechanism remains unknown, recent studies have suggested the involvement of the mammalian target of rapamycin (mTOR) pathway and glycogen synthase kinase-3 (GSK-3) signal, respectively, in the process of ketamine exerting antidepressant actions. This study aimed to investigate the mechanism by which ketamine phosphorylates GSK-3β in the rat prefrontal cortex (PFC) via applying vehicle or the antagonists of mTOR signalling pathway proteins including PI3K/Akt, mTOR and p70S6 kinase to the rats in the forced swimming test (FST) prior to ketamine administration, and subsequently observing the levels of phosphorylated GSK-3β, mTOR and p70S6K in rat PFC as well as the immobility time of rats in the FST. Our results revealed that compared to treatment with vehicle, ketamine increased the levels of phosphorylated GSK-3β in rat PFC (p < 0.05), which was attenuated by PI3K/Akt antagonist pretreatment (p < 0.05), but could not be affected by mTOR antagonist or p70S6K antagonist pretreatment. In addition, all the antagonists reversed the ketamine-induced increases in the phosphorylation of mTOR and p70S6K (p < 0.05). They also all abolished the rapid-acting antidepressant actions of ketamine demonstrated by the increased immobility time of rats in the FST. In conclusion, Akt mediates the phosphorylation of GSK-3β in rat PFC during the process of ketamine exerting rapid antidepressant actions.

Mechanisms of ketamine action as an antidepressant

“…Phosphorylation of GSK-3 might be caused by ketamine-induced activation of the mTOR upstream kinase Akt, which regulates the activity of GSK-3 188 . This is supported by the finding that PI3K/Akt antagonism prevented ketamine-induced phosphorylation of GSK-3β and mTORC1, and abolished ketamine’s antidepressant actions 189 .…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…GSK-3, which has two isoforms, α and β, with similar but not identical functions, has been extensively linked with the antidepressant actions of lithium [346, 347] and has been implicated in the rapid antidepressant actions of ketamine [51]. Ketamine administration increases the levels of phosphorylated GSK-3β (Ser 9) in the PFC and/or hippocampus in rodents [39, 51, 348]. Mice carrying a knock-in mutation of both α and β isoforms of GSK-3 that prevents their kinase activity do not show antidepressant behavioral responses to ketamine [51], and lack ketamine-induced upregulation of cell surface GluA1 in the hippocampus [349].…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Although one report in adult rats and mice claimed that ketamine showed a transient effect (at 50 mg/kg) in forced swim and tail suspension tests without any persistent antidepressant effect (Popik et al, 2008), many preclinical studies have recently focused on understanding the molecular mechanisms underlying the rapid-onset prolonged antidepressant effects. These studies show that plasticity-related pathways, especially the BDNF signaling pathway, are influenced by ketamine treatment (Duman and Voleti, 2012;Kavalali and Monteggia, 2012;Reus et al, 2014;Yang et al, 2014;Zhou et al, 2014). These effects are dependent on the mammalian target of rapamycin (mTOR) signaling pathway , because they can be blocked by rapamycin.…”

“…Synaptic potentiation appears to underlie the ketamine efficacy also in depressive patients, as suggested by increased cortical excitability measured by means of magnetoencephalography (Cornwell et al, 2012). Importantly, AMPAR antagonists have been shown to prevent the antidepressant effects of ketamine in rodents, suggesting that AMPAR activation is required for more persistent antidepressant effects that are at least partly mediated by upregulation of mTOR and BDNF pathways (Koike et al, 2011;Koike and Chaki, 2014;Zhou et al, 2014).…”