NMDA-receptor independent actions of ketamine: a new chapter in a story that’s not so old

Wray, Nathan; Rasenick, Mark M.

doi:10.1038/s41386-018-0201-y

Cited by 6 publications

(3 citation statements)

References 6 publications

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“…NMDA receptor antagonists did not show the rapid, effective, and long-lasting antidepressant effect that resembles ketamine [55]. Thus, ketamine effects that are independent of NMDA receptors have become a focus of research [56]. Here, we found that ketamine increased the activity of GSK-3β.…”

Section: Discussionmentioning

confidence: 69%

Ketamine impairs growth cone and synaptogenesis in human GABAergic projection neurons via GSK-3β and HDAC6 signaling

Saiyin

Chen

et al. 2022

Mol Psychiatry

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The growth cone guides the axon or dendrite of striatal GABAergic projection neurons that protrude into the midbrain and cortex and form complex neuronal circuits and synaptic networks in a developing brain, aberrant projections and synaptic connections in the striatum related to multiple brain disorders. Previously, we showed that ketamine, an anesthetic, reduced dendritic growth, dendritic branches, and spine density in human striatal GABAergic neurons. However, whether ketamine affects the growth cone, the synaptic connection of growing striatal GABAergic neurons has not been tested. Using human GABAergic projection neurons derived from human inducible pluripotent stem cells (hiPSCs) and embryonic stem cells (ES) in vitro, we tested ketamine effects on the growth cones and synapses in developing GABAergic neurons by assessing the morphometry and the glycogen synthase kinase-3 (GSK-3) and histone deacetylase 6 (HDAC6) pathway. Ketamine exposure impairs growth cone formation, synaptogenesis, dendritic development, and maturation via ketamine-mediated activation of GSK-3 pathways and inhibiting HDAC6, an essential stabilizing protein for dendritic morphogenesis and synapse maturation. Our findings identified a novel ketamine neurotoxic pathway that depends on GSK-3β and HDAC6 signaling, suggesting that microtubule acetylation is a potential target for reducing ketamine’s toxic effect on GABAergic projection neuronal development.

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Section: Discussionmentioning

confidence: 69%

Ketamine impairs growth cone and synaptogenesis in human GABAergic projection neurons via GSK-3β and HDAC6 signaling

Saiyin

Chen

et al. 2022

Mol Psychiatry

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“…Interestingly, in the hypothalamus, PC ae C36:5 decreased following either ketamine or (2 R ,6 R )-HNK treatment, and PC aa C36:6 also decreased following (2 R ,6 R )-HNK treatment. A reduction in the relative abundance of several PC species in the prefrontal cortex of rats was found after administration of the antidepressants maprotiline and paroxetine [ 82 , 88 ]. Paroxetine also increased levels of cholesterol and TGs, whereas fluoxetine decreased cholesterol and TG levels [ 89 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration

et al. 2022

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Subanesthetic-dose racemic (R,S)-ketamine (ketamine) produces rapid, robust, and sustained antidepressant effects in major depressive disorder (MDD) and bipolar disorder (BD) and has also been shown to effectively treat neuropathic pain, complex regional pain syndrome, and post-traumatic stress disorder (PTSD). However, to date, its mechanism of action remains unclear. Preclinical studies found that (2 R,6 R;2 S,6 S)-hydroxynorketamine (HNK), a major circulating metabolite of ketamine, elicits antidepressant effects similar to those of ketamine. To help determine how (2 R,6 R)-HNK contributes to ketamine’s mechanism of action, an exploratory, targeted, metabolomic analysis was carried out on plasma and CSF of nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg). A parallel targeted metabolomic analysis in plasma, hippocampus, and hypothalamus was carried out in mice receiving either 10 mg/kg of ketamine, 10 mg/kg of (2 R,6 R)-HNK, or saline. Ketamine and (2 R,6 R)-HNK both affected multiple pathways associated with inflammatory conditions. In addition, several changes were unique to either the healthy human volunteers and/or the mouse arm of the study, indicating that different pathways may be differentially involved in ketamine’s effects in mice and humans. Mechanisms of action found to consistently underlie the effects of ketamine and/or (2 R,6 R)-HNK across both the human metabolome in plasma and CSF and the mouse arm of the study included LAT1, IDO1, NAD+, the nitric oxide (NO) signaling pathway, and sphingolipid rheostat.

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“…These data suggest that the effects of ketamine on the brain might be dose-dependent and its actual effect is less obvious. Apart the well-described inhibition of the NMDA receptors ( Autry et al, 2011 ), ketamine seems to have a plethora of different target sites, from sodium channels to cholinergic, dopamine, and opioid receptors ( Wray and Rasenick, 2019 ) ( Sleigh et al, 2014 ): this makes characterization of the molecular and cellular pathways involved challenging.…”

Section: Limitationsmentioning

confidence: 99%

Minimally invasive protocols and quantification for microglia-mediated perineuronal net disassembly in mouse brain

Venturino

Siegert

2021

STAR Protocols

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Summary Enzymatic digestion of the extracellular matrix with chondroitinase-ABC reinstates juvenile-like plasticity in the adult cortex as it also disassembles the perineuronal nets (PNNs). The disadvantage of the enzyme is that it must be applied intracerebrally and it degrades the ECM for several weeks. Here, we provide two minimally invasive and transient protocols for microglia-enabled PNN disassembly in mouse cortex: repeated treatment with ketamine-xylazine-acepromazine (KXA) anesthesia and 60-Hz light entrainment. We also discuss how to analyze PNNs within microglial endosomes-lysosomes. For complete details on the use and execution of this protocol, please refer to Venturino et al. (2021) .

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NMDA-receptor independent actions of ketamine: a new chapter in a story that’s not so old

Cited by 6 publications

References 6 publications

Ketamine impairs growth cone and synaptogenesis in human GABAergic projection neurons via GSK-3β and HDAC6 signaling

Ketamine impairs growth cone and synaptogenesis in human GABAergic projection neurons via GSK-3β and HDAC6 signaling

Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration

Minimally invasive protocols and quantification for microglia-mediated perineuronal net disassembly in mouse brain

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