Ketamine has shown antidepressant effects in patients with major depressive disorder (MDD) resistant to first‐line treatments and approved for use in this patient population. Ketamine induces several forms of synaptic plasticity, which are proposed to underlie its antidepressant effects. However, the molecular mechanism of action directly responsible for ketamine's antidepressant effects remains under active investigation. It was recently demonstrated that the effectors of the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway, namely, eukaryotic initiation factor 4E (eIF4E) binding proteins 1 and 2 (4E‐BP1 and 4E‐BP2), are central in mediating ketamine‐induced synaptic plasticity and behavioural antidepressant‐like effect. 4E‐BPs are a family of messenger ribonucleic acid (mRNA) translation repressors inactivated by mTORC1. We observed that their expression in inhibitory interneurons mediates ketamine's effects in the forced swim and novelty suppressed feeding tests and the long‐lasting inhibition of GABAergic neurotransmission in the hippocampus. In addition, another effector pathway that regulates translation elongation downstream of mTORC1, the eukaryotic elongation factor 2 kinase (eEF2K), has been implicated in ketamine's behavioural effects. We will discuss how ketamine's rapid antidepressant effect depends on the activation of neuronal mRNA translation through 4E‐BP1/2 and eEF2K. Furthermore, given that these pathways also regulate cognitive functions, we will discuss the evidence of ketamine's effect on cognitive function in MDD. Overall, the data accrued from pre‐clinical research have implicated the mRNA translation pathways in treating mood symptoms of MDD. However, it is yet unclear whether the pro‐cognitive potential of subanesthetic ketamine in rodents also engages these pathways and whether such an effect is consistently observed in the treatment‐resistant MDD population.
Major depressive disorder (MDD) is a disabling mental disorder characterized by negative mood and suicidality. The NMDA antagonist ketamine has been found to reduce depressive symptoms and suicidal thoughts in patients unresponsive to first-line antidepressants, but ketamine's mechanism of action remains unclear.More women are diagnosed with MDD than men and present with greater suicidal ideation, but it is unclear if there are sex-dependent responses to ketamine.It was recently determined that activating mRNA translation via phosphorylation of the eukaryotic initiation factor 4E binding proteins (4E-BPs) is a crucial mechanism of ketamine's antidepressant effect in non-stressed male mice. The aim is to understand if stressed females also engage this mechanism following ketamine treatment. After investigating whether 4E-BP1 and 4E-BP2 are relevant to ketamine's antidepressant mechanisms of action in female mice, the present study's findings are inconclusive, as ketamine had no effect on several chronic variable stress-induced behaviors in tested mice.
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