Antidepressant actions of ketamine engage cell-specific translation via eIF4E

Abstract

Effective pharmacotherapy for major depressive disorder remains a major challenge, as more than 30% of patients are resistant to the first line of treatment (selective serotonin reuptake inhibitors) 1 . Sub-anaesthetic doses of ketamine, a noncompetitive N-methyl-d-aspartate receptor antagonist 2,3 , provide rapid and long-lasting antidepressant effects in these patients [4][5][6] , but the molecular mechanism of these effects remains unclear 7,8 . Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) 9 . The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase 10,11 . mTORC1 controls various neuronal functions 12 , particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs) 13 . Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1-4E-BP signalling in pyramidal excitatory cells of the cortex 8,14 . To test this hypothesis, we studied the behavioural response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamineinduced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission. Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine.A single sub-anaesthetic dose of ketamine elicits a rapid (within hours) and sustained (up to seven days) antidepressant response in patients with treatment-resistant major depressive disorder (MDD) [4][5][6] , serving as the basis for the approval of the enantiomer (S)-ketamine (esketamine) by the FDA for treatment of MDD. Ketamine may exert its antidepressant effects via one of its metabolites, (2R,6R)-HNK 9 , which may act as an inhibitor of NMDA (N-methyl-d-aspartate) receptors at certain concentrations 9,15,16 . Ketamine and (2R,6R)-HNK activate mTORC1 signalling and protein synthesis in the prefrontal cortex (PFC) and hippocampus (HPC) 7,10,11,[17][18][19][20] . Furthermore, in rodents, the antidepressant response to ketamine and (2R,6R)-HNK is blocked by infusion of rapamycin, an allosteric inhibitor of mTORC1, into the PFC 10,11 . mTORC1 affects cellular functions as diverse as nucleotide and lipid synthesis, glucose metabolism, autophagy, lysosome biogenesis, proteasome as...

Ketamine decreases neuronally released glutamate via retrograde stimulation of presynaptic adenosine A1 receptors

“…Therefore, the obtained fluorescent signal is directly proportional to presynaptic activity [43]. As shown, acute (5,15,30 or (2 R, 6 R)-HNK treatment attenuates both KCl-evoked (Fig. 2a, b; Supplementary Fig.…”

“…Extensive research has led to development of several models of ketamine's and (2 R, 6 R)-HNK's antidepressant mechanisms, involving their postsynaptic action to potentiate BDNF [10], AMPA [11,12] and dopamine D1 [13,14] receptor functions. This results in modulation of neuroplasticity pathways, including activation of mTORC1 kinase/eukaryotic initiation factor 4E-binding protein signaling [12,15] and inhibition of eEF2 kinase [10] along with increased dendritic spine formation [12,13,16]. However, few studies have addressed direct effects of ketamine on presynaptic neurotransmission.…”

Determination of Diffusion Kinetics of Ketamine in Brain Tissue: Implications for in vitro Mechanistic Studies of Drug Actions

“…In addition to exerting a blocking effect on NMDA receptors, ketamine is reported to enhance AMPA receptor-mediated synaptic responses (Duman, 2014). Previous studies suggest, this LTP-like effect can be achieved in the presence or in the absence of electrical stimulation, e.g., no synaptic responses evoked during ketamine application (Autry et al, 2011;Aguilar-Valles et al, 2020). We used the "no-stimulation protocol" to assess the effect of a range of ketamine concentrations (2-20 µM) on synaptic strength.…”

“…Previous electrophysiological investigations examining ketamine’s effects at the synaptic receptor level have administered anywhere from 5 to 50 μM ketamine to brain slices via aCSF. Factoring in our experimentally determined partition coefficient, that represents dosages ranging from ∼15 to 150 μM, far exceeding the concentration thought to be relevant to ketamine’s antidepressant effects ( Autry et al, 2011 ; Suzuki et al, 2017 ; Yang et al, 2018 ; Aguilar-Valles et al, 2020 ). Due to the concentration-dependent nature of ketamine’s spectrum of actions, unintended overdosing of ketamine could lead to effects which are vastly different from those responsible for ketamine’s antidepressant actions.…”

A Multiscale View of the Mechanisms Underlying Ketamine’s Antidepressant Effects: An Update on Neuronal Calcium Signaling

“…Local release of BDNF is thought to activate TrkB on the postsynaptic membrane, stimulating the ERK and PI3K-Akt signaling pathways and mammalian target of rapamycin complex 1 (mTORC1) phosphorylation to promote synapse formation by stimulating synaptic proteins, such as GluA1 and PSD-95, which are required for synaptic plasticity ( Cavalleri et al, 2018 ). Recently, mTORC1 effectors 4E-BP2 and 4-EB2 in excitatory or inhibitory neurons underlie behavioral and neurobiological responses to ketamine ( Aguilar-Valles et al, 2021 ). Ketamine-induced activation of TrkB increases GSK-3β phosphorylation via the ERK signaling pathway, decreasing PSD-95 phosphorylation and internalizing the AMPA GluA1 subunit, which upregulates signaling through the GluA1 to promote synapse formation ( Liu et al, 2013 ; Beurel et al, 2016 ).…”