Genome-wide translating mRNA analysis following ketamine reveals novel targets for antidepressant treatment

Miller, Oliver H.; Grabole, Nils; Wells, Isabelle; Hall, Benjamin J.

doi:10.1101/254904

Cited by 4 publications

(4 citation statements)

References 60 publications

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“…In contrast, our RNA seq data revealed a significant increase in the expression of VIPR2 in the PLc. This extends a previous finding showing this following acute ketamine administration [76], to indicate that VIPR2 expression is also increased after sub-chronic ketamine administration. VIPR2 is expressed in somatostatinpositive interneurons and increases excitability of these interneurons [76].…”

Section: Proposed Mechanism Of Action Of Ketamine On Dopamine Synthessupporting

confidence: 90%

“…This extends a previous finding showing this following acute ketamine administration [76], to indicate that VIPR2 expression is also increased after sub-chronic ketamine administration. VIPR2 is expressed in somatostatinpositive interneurons and increases excitability of these interneurons [76]. This finding highlights that other GABAergic interneurons may be affected by sub-chronic ketamine treatment and the need for further work to determine if expression changes in these interneurons, or others that we were not able to measure such as calretinin positive interneurons, contribute to ketamine's effects on dopamine regulation and behaviour.…”

Section: Proposed Mechanism Of Action Of Ketamine On Dopamine Synthessupporting

confidence: 90%

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Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine

et al. 2020

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Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. The mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we develop a translational mouse model of the dopamine pathophysiology seen in schizophrenia and test approaches to reverse the dopamine changes. Mice were treated with sub-chronic ketamine (30 mg/kg) or saline and then received in vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open-field test. In vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen's d = 2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of PV interneurons in prelimbic cortex and ventral subiculum of the hippocampus. Sub-chronic ketamine reduced PV expression in these cortical and hippocampal regions. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1) and 5-HT 1A receptors but no appreciable action at dopamine D 2 receptors, significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, that this requires activation of midbrain dopamine neurons, and can be ameliorated by activating PV interneurons and by a TAAR1/5-HT 1A agonist. This identifies novel therapeutic approaches for targeting presynaptic dopamine dysfunction in patients with schizophrenia and effects of ketamine relevant to its therapeutic use for treating major depression.

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Section: Proposed Mechanism Of Action Of Ketamine On Dopamine Synthessupporting

confidence: 90%

Section: Proposed Mechanism Of Action Of Ketamine On Dopamine Synthessupporting

confidence: 90%

Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine

et al. 2020

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“…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 .…”

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confidence: 99%

Antidepressant actions of ketamine engage cell-specific translation via eIF4E

Aguilar‐Valles

Gregorio

Matta‐Camacho

et al. 2020

Nature

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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...

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“…KLF2 protein is implicated in lung development, embryonic erythropoiesis, epithelial integrity, T-cell viability and adipogenesis (31). Another study by Miller et al (32) was performed using ribosome-bound mRNA footprinting and deep sequencing, and confirmed that initiation of protein synthesis is a defining feature of antidepressant dose ketamine in mice; with the use of GO analysis, vasoactive intestinal peptide receptor 2 gene was identified as a potential target for antidepressant action. In the current study, Klf2 was involved in more pairs in the PPI network of DEGs in the striatum samples treated with ketamine, phencyclidine or memantine compared with normal samples.…”

Section: Discussionmentioning

confidence: 92%

Investigation of the underling mechanism of ketamine for antidepressant effects in treatment‑refractory affective disorders via molecular profile analysis

Qiao

Sun

et al. 2019

Exp Ther Med

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Ketamine elicits a rapid antidepressant effect in treatment-refractory affective disorders. The aim of the present study was to elucidate the underlying mechanism of this effect and to identify potential targets of ketamine for antidepressant effects. GSE73798 and GSE73799 datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in hippocampus or striatum samples treated with ketamine, phencyclidyne or memantine compared with a saline or normal group at 1, 2, 4 and 8 h. The overlapping DEGs were the DEGs in both hippocampus and striatum samples. Kyoto Encyclopedia of Genes and Genomes and BioCyc databases were used to perform functional annotation and pathway analyses. Protein-protein interactions (PPIs) were predicted using Search Tool for the Retrieval of Interacting Genes/Proteins version 9.1 for the DEGs in the striatum samples treated with ketamine, phencyclidine or memantine compared with normal samples. Reverse transcription-quantitative polymerase chain reaction was performed to determine mRNA levels. Perilipin 4 (Plin4) , serum/glucocorticoid regulated kinase 1 (Sgk1) , kruppel like factor 2 (Klf2) and DDB1 and CUL4 associated factor 12 like 1 (Dcaf12l1) were the overlapping DEGs in the striatum samples treated with the three drugs at different time points. The mRNA expression levels of Plin4, Sgk1 and Klf2 were significantly higher (P<0.05), and the mRNA expression level of Dcaf12l1 was significantly lower in the striatum samples of the ketamine-treated group compared with the control group in an in vivo experiment. Both Sgk1 and Klf2 were enriched in the ‘forkhead box O (FoxO) signaling pathway’, and Sgk1 was additionally enriched in the ‘mechanistic target of rapamycin kinase (mTOR) signaling pathway’. PPI networks of DEGs in the striatum samples treated with ketamine, phencyclidine and memantine compared with normal samples were constructed, and Klf2 was involved in more pairs and was therefore a gene hub in the three networks. The four genes, Plin4, Sgk1, Klf2 and Dcaf12l1 , were differentially expressed in all of the groups that treated with the three drugs and their expression levels were verified in in vivo experiments. The FoxO and mTOR signaling pathways may be involved in the underlying mechanism of the antidepressant effects of ketamine, and Plin4, Sgk1, Klf2 and Dcaf12l1 may be potential biomarkers for depression in N-methyl-D-aspartic acid receptor antagonist treatment.

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Genome-wide translating mRNA analysis following ketamine reveals novel targets for antidepressant treatment

Cited by 4 publications

References 60 publications

Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine

Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine

Antidepressant actions of ketamine engage cell-specific translation via eIF4E

Investigation of the underling mechanism of ketamine for antidepressant effects in treatment‑refractory affective disorders via molecular profile analysis

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