NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism

Kiselycznyk, Carly; Jury, Nicholas J.; Halladay, Lindsay R.; Nakazawa, Kazu; Mishina, Masayoshi; Sprengel, Rolf; Grant, Seth G. N.; Svenningsson, Per; Holmes, Andrew

doi:10.1016/j.bbr.2015.03.023

Cited by 50 publications

(39 citation statements)

References 58 publications

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“…In addition, it is also reported that antidepressant effects of Ro 25–6981 were intact in mutants with global GluA1 deletion or GluN1 deletion in forebrain interneurons, but absent in mutants with global deletion of GluN2A. These findings suggest that GluN2B subtype could be a therapeutic target for depression (Kiselycznyk et al, 2015). …”

Section: Discussionmentioning

confidence: 94%

Antidepressant Effects of (+)-MK-801 and (-)-MK-801 in the Social Defeat Stress Model

Yang

Ren

et al. 2016

IJNPPY

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Background:Current data on antidepressant action of the N-methyl-D-aspartate receptor antagonist, (+)-MK-801, is inconsistent. This study was conducted to examine the effects of (+)-MK-801 and its less potent stereoisomer, (-)-MK-801, in the social defeat stress model of depression.Methods:The antidepressant effects of (+)-MK-801 (0.1mg/kg) and (-)-MK-801 (0.1mg/kg) in the social defeat stress model were examined.Results:In the tail suspension and forced swimming tests, both stereoisomers significantly attenuated increased immobility time in susceptible mice. In the sucrose preference test, (+)-MK-801, but not (-)-MK-801, significantly enhanced reduced sucrose consumption 2 or 4 days after a single dose. However, no antianhedonia effects were detected 7 days after a single dose of either stereoisomer.Conclusions:Both stereoisomers of MK-801 induced rapid antidepressant effects in the social defeat stress model, although neither produced a long-lasting effect (7 days).

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Section: Discussionmentioning

confidence: 94%

Antidepressant Effects of (+)-MK-801 and (-)-MK-801 in the Social Defeat Stress Model

Yang

Ren

et al. 2016

IJNPPY

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“…GluN2B-floxed mice were generated as previously described and backcrossed repeatedly to C57BL/6J to produce a congenic background (Brigman et al, 2010). Three separate Cre-driver transgenic lines were used to delete GluN2B in specific brain regions and neuronal subtypes when crossed with the GluN2B-floxed mice: CaMKIIα-Cre (Tsien et al, 1996) to delete GluN2B on cortical and CA1 hippocampal principal neurons (GluN2B CxNULL ) (Brigman et al, 2010), Ppp1r2-Cre (Belforte et al, 2010) to delete GluN2B on forebrain interneurons (predominantly parvalbumin-positive) (GluN2B InterNULL ) (Brigman et al, 2015; Kiselycznyk et al, 2015), and Rgs9-Cre (Dang et al, 2006) to delete GluN2B on striatal medium spiny neurons (GluN2B StNULL ) (Radke et al, 2015b) (Figure 1A). Data from the latter mutants are not reported due to insufficient numbers (see below).…”

Section: Methodsmentioning

confidence: 99%

Reduced ethanol drinking following selective cortical interneuron deletion of the GluN2B NMDA receptors subunit

Radke

Jury

Delpire

et al. 2017

Alcohol

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N -methyl-D-aspartate receptors (NMDAR) are involved in the regulation of alcohol drinking, but the contribution of NMDAR subunits located on specific neuronal populations remains incompletely understood. The current study examined the role of GluN2B-containing NMDARs expressed on cortical principal neurons and cortical interneurons in mouse ethanol (EtOH) drinking. Consumption of escalating concentrations of EtOH was measured in mice with GluN2B gene deletion in either cortical principal neurons (GluN2BCxNULL) or interneurons (GluN2BInterNULL), using a two-bottle choice paradigm. Results showed that GluN2BInterNULL, but not GluN2BCxNULL, mice consumed significantly less EtOH, at relatively high concentrations, than non-mutant controls. In a second paradigm in which mice were offered a 15% EtOH concentration, without escalation, GluN2BCxNULL mice were again no different from controls. These findings provide novel evidence for a contribution of interneuronal GluN2B-containing NMDARs in the regulation of EtOH drinking.

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“…Independent of the mechanism of ketamine action, GluN2B selective antagonists exert rapid antidepressant actions in rodent models 9, 75–78 . Moreover, deletion of GluN2B-containing NMDARs from pyramidal cortical neurons in the brain of mice induced an enhancement of protein synthesis and increased the number of excitatory inputs measured in the prefrontal cortex, concomitant with decreased behavioral despair in the forced-swim test and tail-suspension test, and reduced corticosterone-induced behavioral deficits 71 .…”

Section: Nmdar Inhibition-mediated Mechanismsmentioning

confidence: 99%

Mechanisms of ketamine action as an antidepressant

2018

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Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions in treatment-resistant patients. Although this finding has been met with enthusiasm, ketamine’s widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the unique antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine’s antidepressant actions but lack its undesirable effects. Here, we review hypotheses for the mechanism of action of ketamine as an antidepressant, including direct synaptic or extra-synaptic (GluN2B-selective) NMDAR inhibition, selective inhibition of NMDARs localized on GABAergic interneurons, and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) activation. We also discuss links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of rapamycin (mTOR), and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not involve direct inhibition of the NMDAR, including a role for ketamine’s (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine’s action are not mutually exclusive and may act in a complementary fashion to exert the acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressant behavioral actions. Understanding the molecular mechanisms underpinning ketamine’s antidepressant actions will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression.

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NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism

Cited by 50 publications

References 58 publications

Antidepressant Effects of (+)-MK-801 and (-)-MK-801 in the Social Defeat Stress Model

Antidepressant Effects of (+)-MK-801 and (-)-MK-801 in the Social Defeat Stress Model

Reduced ethanol drinking following selective cortical interneuron deletion of the GluN2B NMDA receptors subunit

Mechanisms of ketamine action as an antidepressant

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