Two cellular hypotheses explaining the initiation of ketamine's antidepressant actions: Direct inhibition and disinhibition

Miller, Oliver H.; Moran, Jacqueline T.; Hall, Benjamin J.

doi:10.1016/j.neuropharm.2015.07.028

Cited by 178 publications

(178 citation statements)

References 96 publications

(49 reference statements)

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“…http://dx.doi.org/10.1101/254904 doi: bioRxiv preprint first posted online Jan. 31, 2018; 3 of mRNA abundance showed that 100mg/kg treated mice had increased expression of IEGs Jun, Klf2, Fos, and Klf4, but no significant increase in expression of IEGs were observed in the lowdose (3mg/kg) group (Supplemental Figure 2). This is consistent with other mechanisms of induction including engagement of homeostatic plasticity 24,25 .…”

Section: Profiling the Translatome After Antidepressant Ketaminesupporting

confidence: 90%

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

Miller

Grabole

Wells

et al. 2018

Preprint

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Low-dose ketamine is an efficacious antidepressant for treatment-resistant unipolar and bipolar depressed patients. Major Depression Disorder patients receiving a single infusion report elevated mood within two hours, and ketamine's antidepressant effects have been observed as long as seven days post-treatment. In light of this remarkable observation, efforts have been undertaken to "reverse-translate" ketamine's effects to understand its mechanism of action. Major advances have been achieved in understanding the molecular, cellular, and circuit level changes that are initiated by lowdose ketamine. Although enhancement of protein synthesis clearly plays a role, the field lacks a comprehensive understanding of the protein synthesis program initiated after ketamine treatment. Here, using ribosome-bound mRNA footprinting and deep sequencing (RiboSeq), we uncover a genome-wide set of actively translated mRNAs (the translatome) in medial prefrontal cortex after an acute antidepressant-like dose of ketamine. Gene Ontology analysis confirmed that initiation of protein synthesis is a defining feature of antidepressant-dose ketamine in mice and Gene Set Enrichment Analysis points to a role for GPCR signaling, metabolism, vascularization, and structural plasticity in ketamine's effects. One gene, VIPR2, whose protein product VPAC2 acts as a GPCR for the neuropeptide vasoactive intestinal peptide, was characterized in cortex and identified as a potential novel target for antidepressant action.

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Section: Profiling the Translatome After Antidepressant Ketaminesupporting

confidence: 90%

“…One proposed mechanism by which low-dose ketamine might exert its antidepressant effects is by blocking NMDARs on inhibitory interneurons in mPFC and causing cortical disinhibition [22][23][24] peer-reviewed) is the author/funder. All rights reserved.…”

Section: Profiling the Translatome After Antidepressant Ketaminementioning

confidence: 99%

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

Miller

Grabole

Wells

et al. 2018

Preprint

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“…In contrast, the typical antidepressants fluoxetine and desipramine do not stimulate phospho-ERK, phospho-S6K, and BDNF release within this rapid time frame, providing pharmacological specificity for the rapid agents. It has also been hypothesized that the rapid actions of ketamine in vivo are activity independent and result from NMDA receptor dependent homeostatic responses that increase the expression of BDNF in the absence of neuronal activity (Autry et al, 2011; Kavalali and Monteggia, 2015; Miller et al, 2016). Further studies will be required to determine the exact role of GABAergic neurons vs. direct effects on glutamatergic neurons in the rapid AMPA-BDNF dependent actions of these agents.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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Recent preclinical and clinical studies demonstrate that three functionally different compounds, the NMDA receptor channel blocker ketamine, mGlu2/3 receptor antagonist LY341495, and NMDA receptor glycine site agent GLYX-13 produce rapid and long lasting antidepressant effects. Furthermore, these agents are reported to stimulate ERK and mTORC1 signaling in brain. Here we used rat primary cortical culture neurons to further examine the cellular actions of these agents. The results demonstrate that low concentrations of all three compounds rapidly increase levels of the phosphorylated and activated forms of ERK and a downstream target of mTORC1, p70S6 kinase, in a concentration and time dependent manner. In addition, each compound rapidly increases BDNF release into the culture media. Further studies demonstrate that induction of BDNF release, as well as stimulation of phospho-ERK is blocked by incubation with an AMPA receptor antagonist. The requirement for AMPA receptor stimulation suggests that the effects of these rapid agents are activity dependent. This possibility is supported by studies demonstrating that neuronal silencing, via incubation with the GABAA receptor agonist muscimol, completely blocks phospho-ERK and BDNF release by each agent. Finally, incubation with each drug for 24 hr increases the number and length of neuronal branches. Together, the results demonstrate that these three different rapid acting antidepressant agents increase ERK signaling and BDNF release in an activity dependent manner that leads to increased neuronal complexity. Further studies will be required to determine the exact mechanisms underlying these effects in cultured neurons and in rodent models.

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“…However, a major question in the field is, what are the initial cellular targets that mediate the increase in glutamate transmission, leading to increased synapse formation and rapid antidepressant behavior (10,20,21)? One hypothesis is that scopolamine blocks muscarinic receptors on GABAergic interneurons, resulting in disinhibition of pyramidal neurons and increased glutamate transmission.…”

Section: Introductionmentioning

confidence: 99%

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

Wohleb¹,

Wu²,

Gerhard³

et al. 2016

Journal of Clinical Investigation

129

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R e s e a R c h a R t i c l e2 4 8 2 jci.org Volume 126 Number 7 July 2016 IntroductionMajor depressive disorder (MDD) is a recurring neuropsychiatric illness that affects up to 17% of the population and causes substantial social and economic burdens (1-4). While some patients respond to existing medications, currently available antidepressants take weeks to months to have an effect, and many patients are considered treatment resistant because they fail to respond to 2 or more antidepressants (5). Recent studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine (ACh) receptor (mAChR) antagonist, and ketamine, an NMDA receptor antagonist, produce rapid antidepressant actions (within hours) and are effective even in treatment-resistant MDD patients (6-8). The rapid antidepressant actions of scopolamine and ketamine are dependent on glutamate release and induction of new spine synapses in the medial prefrontal cortex (mPFC) (9-11), effects that directly target the synaptic pathophysiology of MDD and chronic stress (12-19). However, a major question in the field is, what are the initial cellular targets that mediate the increase in glutamate transmission, leading to increased synapse formation and rapid antidepressant behavior (10, 20, 21)? One hypothesis is that scopolamine blocks muscarinic receptors on GABAergic interneurons, resulting in disinhibition of pyramidal neurons and increased glutamate transmission. Alternatively, scopolamine may act directly on pyramidal neurons to enhance synaptic plasticity and produce antidepressant behavioral responses. Recent studies suggest that the M1-type muscarinic ACh receptor (M1-AChR) subtype may mediate the antidepressant actions of scopolamine (9, 22, 23).M1-AChRs are expressed on both GABAergic interneurons and glutamatergic pyramidal neurons in the mPFC and regulate the activity of both cell types (24)(25)(26).In the present study, we used transgenic mice and viralmediated gene transfer to drive Cre-dependent expression of M1-AChR shRNA in different subtypes of GABA interneurons or glutamate neurons in the mPFC. The results demonstrate that M1-AChR knockdown in GABA interneurons, but not pyramidal neurons, blocks the antidepressant-like response to scopolamine in mouse behavioral models. In addition, we show that knockdown of M1-AChR in somatostatin (SST), but not parvalbumin (PV), interneurons, blocks the actions of scopolamine. These findings reveal that M1-AChRs on SST interneurons in the mPFC are a critical cellular target underlying the rapid antidepressant effects of scopolamine. Results CaMKII+ and GAD + cell type-specific knockdown of M1-AChR in the mPFC. To determine whether glutamatergic pyramidal neurons and GABAergic interneurons in the mPFC express M1-AChR, double immunohistology was conducted with an M1-AChR antibody and Ca 2+ /calmodulin-dependent kinase II (CaMKII; pyramidal cell) or glutamate decarboxylase-67 (GAD67; GABA interneuron) (25). The results show that CaMKII + pyramidal neurons display punctate M1-AChR labeling in the mPF...

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Two cellular hypotheses explaining the initiation of ketamine's antidepressant actions: Direct inhibition and disinhibition

Cited by 178 publications

References 96 publications

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

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

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

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

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