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A CRHR1 antagonist prevents synaptic loss and memory deficits in a trauma-induced delirium-like syndrome
Older patients with severe physical trauma are at high risk of developing neuropsychiatric syndromes with global impairment of cognition, attention, and consciousness. We employed a thoracic trauma (TxT) mouse model and thoroughly analyzed age-dependent spatial and temporal posttraumatic alterations...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550963/ https://www.ncbi.nlm.nih.gov/pubmed/32051550 http://dx.doi.org/10.1038/s41380-020-0659-y |
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author | Cursano, Silvia Battaglia, Chiara R. Urrutia-Ruiz, Carolina Grabrucker, Stefanie Schön, Michael Bockmann, Jürgen Braumüller, Sonja Radermacher, Peter Roselli, Francesco Huber-Lang, Markus Boeckers, Tobias M. |
author_facet | Cursano, Silvia Battaglia, Chiara R. Urrutia-Ruiz, Carolina Grabrucker, Stefanie Schön, Michael Bockmann, Jürgen Braumüller, Sonja Radermacher, Peter Roselli, Francesco Huber-Lang, Markus Boeckers, Tobias M. |
author_sort | Cursano, Silvia |
collection | PubMed |
description | Older patients with severe physical trauma are at high risk of developing neuropsychiatric syndromes with global impairment of cognition, attention, and consciousness. We employed a thoracic trauma (TxT) mouse model and thoroughly analyzed age-dependent spatial and temporal posttraumatic alterations in the central nervous system. Up to 5 days after trauma, we observed a transient 50% decrease in the number of excitatory synapses specifically in hippocampal pyramidal neurons accompanied by alterations in attention and motor activity and disruption of contextual memory consolidation. In parallel, hippocampal corticotropin-releasing hormone (CRH) expression was highly upregulated, and brain-derived neurotrophic factor (BDNF) levels were significantly reduced. In vitro experiments revealed that CRH application induced neuronal autophagy with rapid lysosomal degradation of BDNF via the NF-κB pathway. The subsequent synaptic loss was rescued by BDNF as well as by specific NF-κB and CRH receptor 1 (CRHR1) antagonists. In vivo, the chronic application of a CRHR1 antagonist after TxT resulted in reversal of the observed histological, molecular, and behavioral alterations. The data suggest that neuropsychiatric syndromes (i.e., delirium) after peripheral trauma might be at least in part due to the activation of the hippocampal CRH/NF-κB/BDNF pathway, which results in a dramatic loss of synaptic contacts. The successful rescue by stress hormone receptor antagonists should encourage clinical trials focusing on trauma-induced delirium and/or other posttraumatic syndromes. |
format | Online Article Text |
id | pubmed-8550963 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85509632021-11-10 A CRHR1 antagonist prevents synaptic loss and memory deficits in a trauma-induced delirium-like syndrome Cursano, Silvia Battaglia, Chiara R. Urrutia-Ruiz, Carolina Grabrucker, Stefanie Schön, Michael Bockmann, Jürgen Braumüller, Sonja Radermacher, Peter Roselli, Francesco Huber-Lang, Markus Boeckers, Tobias M. Mol Psychiatry Article Older patients with severe physical trauma are at high risk of developing neuropsychiatric syndromes with global impairment of cognition, attention, and consciousness. We employed a thoracic trauma (TxT) mouse model and thoroughly analyzed age-dependent spatial and temporal posttraumatic alterations in the central nervous system. Up to 5 days after trauma, we observed a transient 50% decrease in the number of excitatory synapses specifically in hippocampal pyramidal neurons accompanied by alterations in attention and motor activity and disruption of contextual memory consolidation. In parallel, hippocampal corticotropin-releasing hormone (CRH) expression was highly upregulated, and brain-derived neurotrophic factor (BDNF) levels were significantly reduced. In vitro experiments revealed that CRH application induced neuronal autophagy with rapid lysosomal degradation of BDNF via the NF-κB pathway. The subsequent synaptic loss was rescued by BDNF as well as by specific NF-κB and CRH receptor 1 (CRHR1) antagonists. In vivo, the chronic application of a CRHR1 antagonist after TxT resulted in reversal of the observed histological, molecular, and behavioral alterations. The data suggest that neuropsychiatric syndromes (i.e., delirium) after peripheral trauma might be at least in part due to the activation of the hippocampal CRH/NF-κB/BDNF pathway, which results in a dramatic loss of synaptic contacts. The successful rescue by stress hormone receptor antagonists should encourage clinical trials focusing on trauma-induced delirium and/or other posttraumatic syndromes. Nature Publishing Group UK 2020-02-12 2021 /pmc/articles/PMC8550963/ /pubmed/32051550 http://dx.doi.org/10.1038/s41380-020-0659-y Text en © The Author(s) 2020 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Cursano, Silvia Battaglia, Chiara R. Urrutia-Ruiz, Carolina Grabrucker, Stefanie Schön, Michael Bockmann, Jürgen Braumüller, Sonja Radermacher, Peter Roselli, Francesco Huber-Lang, Markus Boeckers, Tobias M. A CRHR1 antagonist prevents synaptic loss and memory deficits in a trauma-induced delirium-like syndrome |
title | A CRHR1 antagonist prevents synaptic loss and memory deficits in a trauma-induced delirium-like syndrome |
title_full | A CRHR1 antagonist prevents synaptic loss and memory deficits in a trauma-induced delirium-like syndrome |
title_fullStr | A CRHR1 antagonist prevents synaptic loss and memory deficits in a trauma-induced delirium-like syndrome |
title_full_unstemmed | A CRHR1 antagonist prevents synaptic loss and memory deficits in a trauma-induced delirium-like syndrome |
title_short | A CRHR1 antagonist prevents synaptic loss and memory deficits in a trauma-induced delirium-like syndrome |
title_sort | crhr1 antagonist prevents synaptic loss and memory deficits in a trauma-induced delirium-like syndrome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550963/ https://www.ncbi.nlm.nih.gov/pubmed/32051550 http://dx.doi.org/10.1038/s41380-020-0659-y |
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