Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine
Abstract Subanesthetic ketamine evokes rapid antidepressant effects in human patients that persist long past ketamine’s chemical half-life of ~2 h. Ketamine’s sustained antidepressant action may be due to modulation of cortical plasticity. We find that ketamine ameliorates depression-like behavior i...
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2021-02-01
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Series: | Translational Psychiatry |
Online Access: | https://doi.org/10.1038/s41398-021-01255-4 |
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doaj-8e2bf13b2ac64dbf9a846e76724e24362021-03-11T12:52:29ZengNature Publishing GroupTranslational Psychiatry2158-31882021-02-0111111710.1038/s41398-021-01255-4Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamineSteven F. Grieco0Xin Qiao1Kevin G. Johnston2Lujia Chen3Renetta R. Nelson4Cary Lai5Todd C. Holmes6Xiangmin Xu7Department of Anatomy and Neurobiology, School of Medicine, University of CaliforniaDepartment of Anatomy and Neurobiology, School of Medicine, University of CaliforniaDepartment of Mathematics, University of CaliforniaDepartment of Anatomy and Neurobiology, School of Medicine, University of CaliforniaDepartment of Anatomy and Neurobiology, School of Medicine, University of CaliforniaDepartment of Psychological and Brain Sciences, Indiana UniversityDepartment of Physiology and Biophysics, School of Medicine, Universityof CaliforniaDepartment of Anatomy and Neurobiology, School of Medicine, University of CaliforniaAbstract Subanesthetic ketamine evokes rapid antidepressant effects in human patients that persist long past ketamine’s chemical half-life of ~2 h. Ketamine’s sustained antidepressant action may be due to modulation of cortical plasticity. We find that ketamine ameliorates depression-like behavior in the forced swim test in adult mice, and this depends on parvalbumin-expressing (PV) neuron-directed neuregulin-1 (NRG1)/ErbB4 signaling. Ketamine rapidly downregulates NRG1 expression in PV inhibitory neurons in mouse medial prefrontal cortex (mPFC) following a single low-dose ketamine treatment. This NRG1 downregulation in PV neurons co-tracks with the decreases in synaptic inhibition to mPFC excitatory neurons for up to a week. This results from reduced synaptic excitation to PV neurons, and is blocked by exogenous NRG1 as well as by PV targeted ErbB4 receptor knockout. Thus, we conceptualize that ketamine’s effects are mediated through rapid and sustained cortical disinhibition via PV-specific NRG1 signaling. Our findings reveal a novel neural plasticity-based mechanism for ketamine’s acute and long-lasting antidepressant effects.https://doi.org/10.1038/s41398-021-01255-4 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Steven F. Grieco Xin Qiao Kevin G. Johnston Lujia Chen Renetta R. Nelson Cary Lai Todd C. Holmes Xiangmin Xu |
spellingShingle |
Steven F. Grieco Xin Qiao Kevin G. Johnston Lujia Chen Renetta R. Nelson Cary Lai Todd C. Holmes Xiangmin Xu Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine Translational Psychiatry |
author_facet |
Steven F. Grieco Xin Qiao Kevin G. Johnston Lujia Chen Renetta R. Nelson Cary Lai Todd C. Holmes Xiangmin Xu |
author_sort |
Steven F. Grieco |
title |
Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine |
title_short |
Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine |
title_full |
Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine |
title_fullStr |
Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine |
title_full_unstemmed |
Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine |
title_sort |
neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine |
publisher |
Nature Publishing Group |
series |
Translational Psychiatry |
issn |
2158-3188 |
publishDate |
2021-02-01 |
description |
Abstract Subanesthetic ketamine evokes rapid antidepressant effects in human patients that persist long past ketamine’s chemical half-life of ~2 h. Ketamine’s sustained antidepressant action may be due to modulation of cortical plasticity. We find that ketamine ameliorates depression-like behavior in the forced swim test in adult mice, and this depends on parvalbumin-expressing (PV) neuron-directed neuregulin-1 (NRG1)/ErbB4 signaling. Ketamine rapidly downregulates NRG1 expression in PV inhibitory neurons in mouse medial prefrontal cortex (mPFC) following a single low-dose ketamine treatment. This NRG1 downregulation in PV neurons co-tracks with the decreases in synaptic inhibition to mPFC excitatory neurons for up to a week. This results from reduced synaptic excitation to PV neurons, and is blocked by exogenous NRG1 as well as by PV targeted ErbB4 receptor knockout. Thus, we conceptualize that ketamine’s effects are mediated through rapid and sustained cortical disinhibition via PV-specific NRG1 signaling. Our findings reveal a novel neural plasticity-based mechanism for ketamine’s acute and long-lasting antidepressant effects. |
url |
https://doi.org/10.1038/s41398-021-01255-4 |
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