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

Henrik Samuel Kohtala, Wiebke Theilmann, Marko Rosenholm, Leena Penna, Gulsum Karabulut, Salla Uusitalo, Kaija Järventausta, Arvi Yli-Hankala, Ipek Yalcin, Nobuaki Matsui, Henna-Kaisa Wigren, Tomi Rantamäki

Research output: Contribution to journalArticleScientificpeer-review

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 kinasemarkers of neuronal excitabilitywere upregulated during N2O exposure. Notably, phosphorylation of BDNF receptor TrkB and GSK3 (glycogen synthase kinase 3) 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-GSK3 signaling was further strengthened utilizing medetomidine, a hypnotic-sedative agent that facilitates slow oscillations directly through the activation of (2)-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 GSK3 signaling during homeostatic emergence of slow oscillations are critical components for rapid antidepressant responses.
Original languageEnglish
JournalMolecular Neurobiology
Volume56
Issue number6
Pages (from-to)4163-4174
Number of pages12
ISSN0893-7648
DOIs
Publication statusPublished - Jun 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3124 Neurology and psychiatry
  • 3111 Biomedicine
  • Rapid-acting antidepressant
  • Nitrous oxide
  • Ketamine
  • Cortical excitation
  • Electroencephalogram
  • Sedation
  • GLYCOGEN-SYNTHASE KINASE-3
  • NMDA RECEPTOR BLOCKADE
  • ELECTROCONVULSIVE-THERAPY
  • NEUROTROPHIN RECEPTOR
  • SLEEP-DEPRIVATION
  • PREFRONTAL CORTEX
  • NITROUS-OXIDE
  • DELTA-EEG
  • KETAMINE
  • STIMULATION

Cite this

Kohtala, Henrik Samuel ; Theilmann, Wiebke ; Rosenholm, Marko ; Penna, Leena ; Karabulut, Gulsum ; Uusitalo, Salla ; Järventausta, Kaija ; Yli-Hankala, Arvi ; Yalcin, Ipek ; Matsui, Nobuaki ; Wigren, Henna-Kaisa ; Rantamäki, Tomi. / Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses. In: Molecular Neurobiology. 2019 ; Vol. 56, No. 6. pp. 4163-4174.
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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 kinasemarkers of neuronal excitabilitywere upregulated during N2O exposure. Notably, phosphorylation of BDNF receptor TrkB and GSK3 (glycogen synthase kinase 3) 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-GSK3 signaling was further strengthened utilizing medetomidine, a hypnotic-sedative agent that facilitates slow oscillations directly through the activation of (2)-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 GSK3 signaling during homeostatic emergence of slow oscillations are critical components for rapid antidepressant responses.",
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Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses. / Kohtala, Henrik Samuel; Theilmann, Wiebke; Rosenholm, Marko ; Penna, Leena; Karabulut, Gulsum; Uusitalo, Salla; Järventausta, Kaija; Yli-Hankala, Arvi; Yalcin, Ipek; Matsui, Nobuaki; Wigren, Henna-Kaisa; Rantamäki, Tomi.

In: Molecular Neurobiology, Vol. 56, No. 6, 06.2019, p. 4163-4174.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses

AU - Kohtala, Henrik Samuel

AU - Theilmann, Wiebke

AU - Rosenholm, Marko

AU - Penna, Leena

AU - Karabulut, Gulsum

AU - Uusitalo, Salla

AU - Järventausta, Kaija

AU - Yli-Hankala, Arvi

AU - Yalcin, Ipek

AU - Matsui, Nobuaki

AU - Wigren, Henna-Kaisa

AU - Rantamäki, Tomi

PY - 2019/6

Y1 - 2019/6

N2 - 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 kinasemarkers of neuronal excitabilitywere upregulated during N2O exposure. Notably, phosphorylation of BDNF receptor TrkB and GSK3 (glycogen synthase kinase 3) 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-GSK3 signaling was further strengthened utilizing medetomidine, a hypnotic-sedative agent that facilitates slow oscillations directly through the activation of (2)-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 GSK3 signaling during homeostatic emergence of slow oscillations are critical components for rapid antidepressant responses.

AB - 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 kinasemarkers of neuronal excitabilitywere upregulated during N2O exposure. Notably, phosphorylation of BDNF receptor TrkB and GSK3 (glycogen synthase kinase 3) 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-GSK3 signaling was further strengthened utilizing medetomidine, a hypnotic-sedative agent that facilitates slow oscillations directly through the activation of (2)-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 GSK3 signaling during homeostatic emergence of slow oscillations are critical components for rapid antidepressant responses.

KW - 3124 Neurology and psychiatry

KW - 3111 Biomedicine

KW - Rapid-acting antidepressant

KW - Nitrous oxide

KW - Ketamine

KW - Cortical excitation

KW - Electroencephalogram

KW - Sedation

KW - GLYCOGEN-SYNTHASE KINASE-3

KW - NMDA RECEPTOR BLOCKADE

KW - ELECTROCONVULSIVE-THERAPY

KW - NEUROTROPHIN RECEPTOR

KW - SLEEP-DEPRIVATION

KW - PREFRONTAL CORTEX

KW - NITROUS-OXIDE

KW - DELTA-EEG

KW - KETAMINE

KW - STIMULATION

U2 - 10.1007/s12035-018-1364-6

DO - 10.1007/s12035-018-1364-6

M3 - Article

VL - 56

SP - 4163

EP - 4174

JO - Molecular Neurobiology

JF - Molecular Neurobiology

SN - 0893-7648

IS - 6

ER -