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Aberrant glial activation and synaptic defects in CaMKIIα-iCre and nestin-Cre transgenic mouse models
Current scientific research is driven by the ability to manipulate gene expression by utilizing the Cre/loxP system in transgenic mouse models. However, artifacts in Cre-driver mouse lines that introduce undesired effects and confound results are increasingly being reported. Here, we show aberrant n...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9772212/ https://www.ncbi.nlm.nih.gov/pubmed/36543864 http://dx.doi.org/10.1038/s41598-022-26671-4 |
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author | Alia, Alia O. Jeon, Sohee Popovic, Jelena Salvo, Miranda A. Sadleir, Katherine R. Vassar, Robert Cuddy, Leah K. |
author_facet | Alia, Alia O. Jeon, Sohee Popovic, Jelena Salvo, Miranda A. Sadleir, Katherine R. Vassar, Robert Cuddy, Leah K. |
author_sort | Alia, Alia O. |
collection | PubMed |
description | Current scientific research is driven by the ability to manipulate gene expression by utilizing the Cre/loxP system in transgenic mouse models. However, artifacts in Cre-driver mouse lines that introduce undesired effects and confound results are increasingly being reported. Here, we show aberrant neuroinflammation and synaptic changes in two widely used Cre-driver mouse models. Neuroinflammation in CaMKIIα-iCre mice was characterized by the activation and proliferation of microglia and astrocytes in synaptic layers of the hippocampus. Increased GFAP and Iba1 levels were observed in hippocampal brain regions of 4-, 8- and 22-month-old CaMKIIα-iCre mice compared to WT littermates. Synaptic changes in NMDAR, AMPAR, PSD95 and phosphorylated CaMKIIα became apparent in 8-month-old CaMKIIα-iCre mice but were not observed in 4-month-old CaMKIIα-iCre mice. Synaptophysin and synaptoporin were unchanged in CaMKIIα-iCre compared to WT mice, suggesting that synaptic alterations may occur in excitatory postsynaptic regions in which iCre is predominantly expressed. Finally, hippocampal volume was reduced in 22-month-old CaMKIIα-iCre mice compared to WT mice. We tested the brains of mice of additional common Cre-driver mouse models for neuroinflammation; the nestin-Cre mouse model showed synaptic changes and astrocytosis marked by increased GFAP+ astrocytes in cortical and hippocampal regions, while the original CaMKIIα-Cre T29-1 strain was comparable to WT mice. The mechanisms underlying abnormal neuroinflammation in nestin-Cre and CaMKIIα-iCre are unknown but may be associated with high levels of Cre expression. Our findings are critical to the scientific community and demonstrate that the correct Cre-driver controls must be included in all studies using these mice. |
format | Online Article Text |
id | pubmed-9772212 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-97722122022-12-23 Aberrant glial activation and synaptic defects in CaMKIIα-iCre and nestin-Cre transgenic mouse models Alia, Alia O. Jeon, Sohee Popovic, Jelena Salvo, Miranda A. Sadleir, Katherine R. Vassar, Robert Cuddy, Leah K. Sci Rep Article Current scientific research is driven by the ability to manipulate gene expression by utilizing the Cre/loxP system in transgenic mouse models. However, artifacts in Cre-driver mouse lines that introduce undesired effects and confound results are increasingly being reported. Here, we show aberrant neuroinflammation and synaptic changes in two widely used Cre-driver mouse models. Neuroinflammation in CaMKIIα-iCre mice was characterized by the activation and proliferation of microglia and astrocytes in synaptic layers of the hippocampus. Increased GFAP and Iba1 levels were observed in hippocampal brain regions of 4-, 8- and 22-month-old CaMKIIα-iCre mice compared to WT littermates. Synaptic changes in NMDAR, AMPAR, PSD95 and phosphorylated CaMKIIα became apparent in 8-month-old CaMKIIα-iCre mice but were not observed in 4-month-old CaMKIIα-iCre mice. Synaptophysin and synaptoporin were unchanged in CaMKIIα-iCre compared to WT mice, suggesting that synaptic alterations may occur in excitatory postsynaptic regions in which iCre is predominantly expressed. Finally, hippocampal volume was reduced in 22-month-old CaMKIIα-iCre mice compared to WT mice. We tested the brains of mice of additional common Cre-driver mouse models for neuroinflammation; the nestin-Cre mouse model showed synaptic changes and astrocytosis marked by increased GFAP+ astrocytes in cortical and hippocampal regions, while the original CaMKIIα-Cre T29-1 strain was comparable to WT mice. The mechanisms underlying abnormal neuroinflammation in nestin-Cre and CaMKIIα-iCre are unknown but may be associated with high levels of Cre expression. Our findings are critical to the scientific community and demonstrate that the correct Cre-driver controls must be included in all studies using these mice. Nature Publishing Group UK 2022-12-21 /pmc/articles/PMC9772212/ /pubmed/36543864 http://dx.doi.org/10.1038/s41598-022-26671-4 Text en © The Author(s) 2022 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Alia, Alia O. Jeon, Sohee Popovic, Jelena Salvo, Miranda A. Sadleir, Katherine R. Vassar, Robert Cuddy, Leah K. Aberrant glial activation and synaptic defects in CaMKIIα-iCre and nestin-Cre transgenic mouse models |
title | Aberrant glial activation and synaptic defects in CaMKIIα-iCre and nestin-Cre transgenic mouse models |
title_full | Aberrant glial activation and synaptic defects in CaMKIIα-iCre and nestin-Cre transgenic mouse models |
title_fullStr | Aberrant glial activation and synaptic defects in CaMKIIα-iCre and nestin-Cre transgenic mouse models |
title_full_unstemmed | Aberrant glial activation and synaptic defects in CaMKIIα-iCre and nestin-Cre transgenic mouse models |
title_short | Aberrant glial activation and synaptic defects in CaMKIIα-iCre and nestin-Cre transgenic mouse models |
title_sort | aberrant glial activation and synaptic defects in camkiiα-icre and nestin-cre transgenic mouse models |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9772212/ https://www.ncbi.nlm.nih.gov/pubmed/36543864 http://dx.doi.org/10.1038/s41598-022-26671-4 |
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