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Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses
- Source :
- Molecular Neurobiology
- Publication Year :
- 2019
-
Abstract
- Rapid antidepressant effects of ketamine become most evident when its psychotomimetic effects subside, but the neurobiological basis of this “lag” remains unclear. Laughing gas (N2O), another NMDA-R (N-methyl-d-aspartate receptor) blocker, has been reported to bring antidepressant effects rapidly upon drug discontinuation. We took advantage of the exceptional pharmacokinetic properties of N2O to investigate EEG (electroencephalogram) alterations and molecular determinants of antidepressant actions during and immediately after NMDA-R blockade. Effects of the drugs on brain activity were investigated in C57BL/6 mice using quantitative EEG recordings. Western blot and qPCR were used for molecular analyses. Learned helplessness (LH) was used to assess antidepressant-like behavior. Immediate-early genes (e.g., bdnf) and phosphorylation of mitogen-activated protein kinase—markers of neuronal excitability—were upregulated during N2O exposure. Notably, phosphorylation of BDNF receptor TrkB and GSK3β (glycogen synthase kinase 3β) became regulated only gradually upon N2O discontinuation, during a brain state dominated by slow EEG activity. Subanesthetic ketamine and flurothyl-induced convulsions (reminiscent of electroconvulsive therapy) also evoked slow oscillations when their acute pharmacological effects subsided. The correlation between ongoing slow EEG oscillations and TrkB-GSK3β signaling was further strengthened utilizing medetomidine, a hypnotic-sedative agent that facilitates slow oscillations directly through the activation of α2-adrenergic autoreceptors. Medetomidine did not, however, facilitate markers of neuronal excitability or produce antidepressant-like behavioral changes in LH. Our results support a hypothesis that transient cortical excitability and the subsequent regulation of TrkB and GSK3β signaling during homeostatic emergence of slow oscillations are critical components for rapid antidepressant responses. Electronic supplementary material The online version of this article (10.1007/s12035-018-1364-6) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
STIMULATION
Stimulation
Tropomyosin receptor kinase B
PREFRONTAL CORTEX
Electroencephalography
3124 Neurology and psychiatry
ELECTROCONVULSIVE-THERAPY
0302 clinical medicine
NMDA RECEPTOR BLOCKADE
GSK-3
Neurologia ja psykiatria - Neurology and psychiatry
Flurothyl
Homeostasis
Rapid-acting antidepressant
Prefrontal cortex
Cerebral Cortex
Neurons
Nitrous oxide
medicine.diagnostic_test
DELTA-EEG
Cortical excitation
Psychotomimetic
GLYCOGEN-SYNTHASE KINASE-3
Antidepressive Agents
3. Good health
Up-Regulation
Neurology
Sedation
Autoreceptor
Antidepressant
Ketamine
medicine.drug
Farmasia - Pharmacy
Signal Transduction
Neuroscience (miscellaneous)
Article
03 medical and health sciences
Cellular and Molecular Neuroscience
medicine
Animals
Receptor, trkB
Anesthetics
Glycogen Synthase Kinase 3 beta
Dose-Response Relationship, Drug
business.industry
NITROUS-OXIDE
Medetomidine
NEUROTROPHIN RECEPTOR
Mice, Inbred C57BL
Electroencephalogram
030104 developmental biology
3111 Biomedicine
business
Neuroscience
030217 neurology & neurosurgery
SLEEP-DEPRIVATION
Biomarkers
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Molecular Neurobiology
- Accession number :
- edsair.doi.dedup.....75b35478a5c6371b0b67856bf6796eee