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Mol Neurobiol. 2019 Jun;56(6):4163-4174. doi: 10.1007/s12035-018-1364-6. Epub 2018 Oct 4.

Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses.

Author information

1
Faculty of Biological and Environmental Sciences, University of Helsinki, P.O.Box 65, Viikinkaari 1, Helsinki, Finland.
2
Laboratory of Neurotherapeutics, Faculty of Pharmacy, Division of Pharmacology and Pharmacotherapy, University of Helsinki, Viikinkaari 5, P.O. Box 56,, Helsinki, Finland.
3
Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique and Université de Strasbourg, Strasbourg Cedex, France.
4
Department of Anesthesiology and Reanimation, Gazi University, Ankara, Turkey.
5
Department of Psychiatry, Tampere University Hospital, Tampere, Finland.
6
Faculty of Medicine and Life Sciences, Department of Anesthesiology, University of Tampere, Tampere, Finland.
7
Department of Anaesthesia, Tampere University Hospital, Tampere, Finland.
8
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
9
Faculty of Medicine, Medicum/Physiology, University of Helsinki, Helsinki, Finland.
10
Faculty of Biological and Environmental Sciences, University of Helsinki, P.O.Box 65, Viikinkaari 1, Helsinki, Finland. tomi.rantamaki@helsinki.fi.
11
Laboratory of Neurotherapeutics, Faculty of Pharmacy, Division of Pharmacology and Pharmacotherapy, University of Helsinki, Viikinkaari 5, P.O. Box 56,, Helsinki, Finland. tomi.rantamaki@helsinki.fi.

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.

KEYWORDS:

Cortical excitation; Electroencephalogram; Ketamine; Nitrous oxide; Rapid-acting antidepressant; Sedation

PMID:
30288695
DOI:
10.1007/s12035-018-1364-6

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