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Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses
Rapid antidepressant effects of ketamine become most evident when its psychotomimetic effects subside, but the neurobiological basis of this “lag” remains unclear. Laughing gas (N(2)O), another NMDA-R (N-methyl-d-aspartate receptor) blocker, has been reported to bring antidepressant effects rapidly...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505519/ https://www.ncbi.nlm.nih.gov/pubmed/30288695 http://dx.doi.org/10.1007/s12035-018-1364-6 |
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author | Kohtala, 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 |
author_facet | Kohtala, 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 |
author_sort | Kohtala, Samuel |
collection | PubMed |
description | Rapid antidepressant effects of ketamine become most evident when its psychotomimetic effects subside, but the neurobiological basis of this “lag” remains unclear. Laughing gas (N(2)O), 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 N(2)O 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 N(2)O exposure. Notably, phosphorylation of BDNF receptor TrkB and GSK3β (glycogen synthase kinase 3β) became regulated only gradually upon N(2)O 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 α(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 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. |
format | Online Article Text |
id | pubmed-6505519 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-65055192019-05-28 Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses Kohtala, 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 Mol Neurobiol Article Rapid antidepressant effects of ketamine become most evident when its psychotomimetic effects subside, but the neurobiological basis of this “lag” remains unclear. Laughing gas (N(2)O), 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 N(2)O 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 N(2)O exposure. Notably, phosphorylation of BDNF receptor TrkB and GSK3β (glycogen synthase kinase 3β) became regulated only gradually upon N(2)O 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 α(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 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. Springer US 2018-10-04 2019 /pmc/articles/PMC6505519/ /pubmed/30288695 http://dx.doi.org/10.1007/s12035-018-1364-6 Text en © The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Article Kohtala, 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 |
title | Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses |
title_full | Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses |
title_fullStr | Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses |
title_full_unstemmed | Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses |
title_short | Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses |
title_sort | cortical excitability and activation of trkb signaling during rebound slow oscillations are critical for rapid antidepressant responses |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505519/ https://www.ncbi.nlm.nih.gov/pubmed/30288695 http://dx.doi.org/10.1007/s12035-018-1364-6 |
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