CHD8 adulthood microglial knockdown in C57BL6 mice induces behavioral, morphological, and transcriptional changes in a sex-dependent manner
Abstract Mutations in CHD8 (chromodomain-helicase-DNA binding protein 8) are highly associated with autism spectrum disorders. It has been well established that CHD8 has a prominent role in the development of neurons. However, there is little knowledge of its specific roles in microglia, and its pos...
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Nature Publishing Group
2025-07-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03468-3 |
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| author | Orly Weissberg Ram Harari Chizim Dogun Dmitriy Getselter Evan Elliott |
| author_facet | Orly Weissberg Ram Harari Chizim Dogun Dmitriy Getselter Evan Elliott |
| author_sort | Orly Weissberg |
| collection | DOAJ |
| description | Abstract Mutations in CHD8 (chromodomain-helicase-DNA binding protein 8) are highly associated with autism spectrum disorders. It has been well established that CHD8 has a prominent role in the development of neurons. However, there is little knowledge of its specific roles in microglia, and its possible roles in cellular functions after development, i.e. adulthood. In addition, while microglial dysfunction has been characterized in autism, the roles of autism-associated genes in microglial function have not been well characterized. Using conditional knockdown technology in C57BL6 mice models, we determined that adulthood deletion of Chd8 in microglia induces robust changes in behavior, including anxiety, social deficits, and depression-like behavior, in association with changes in microglial activation and robust microglial gene expression changes in the whole brain, including expression of cytokines. Of great interest, many of these changes were seen specifically in male deletion mice, and not female deletion mice. In contrast, adulthood neuron knockdown had more subtle effects on behavior, mainly on depression-like behavior in males. In addition, neuronal knockdown leads to upregulation of genes associated with Hedgehog and Wnt/Beta-catenin pathways in the hippocampus specifically in males. In summary, CHD8 is particularly important for microglial function in adulthood and has cellular effects that are specific to males in C57BL6 mice. |
| format | Article |
| id | doaj-art-8f16168d92f04c3a8f8917b94fda343c |
| institution | Kabale University |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
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| series | Translational Psychiatry |
| spelling | doaj-art-8f16168d92f04c3a8f8917b94fda343c2025-08-20T04:02:41ZengNature Publishing GroupTranslational Psychiatry2158-31882025-07-0115111610.1038/s41398-025-03468-3CHD8 adulthood microglial knockdown in C57BL6 mice induces behavioral, morphological, and transcriptional changes in a sex-dependent mannerOrly Weissberg0Ram Harari1Chizim Dogun2Dmitriy Getselter3Evan Elliott4Azrieli Faculty of Medicine, Bar Ilan UniversityAzrieli Faculty of Medicine, Bar Ilan UniversityAzrieli Faculty of Medicine, Bar Ilan UniversityAzrieli Faculty of Medicine, Bar Ilan UniversityAzrieli Faculty of Medicine, Bar Ilan UniversityAbstract Mutations in CHD8 (chromodomain-helicase-DNA binding protein 8) are highly associated with autism spectrum disorders. It has been well established that CHD8 has a prominent role in the development of neurons. However, there is little knowledge of its specific roles in microglia, and its possible roles in cellular functions after development, i.e. adulthood. In addition, while microglial dysfunction has been characterized in autism, the roles of autism-associated genes in microglial function have not been well characterized. Using conditional knockdown technology in C57BL6 mice models, we determined that adulthood deletion of Chd8 in microglia induces robust changes in behavior, including anxiety, social deficits, and depression-like behavior, in association with changes in microglial activation and robust microglial gene expression changes in the whole brain, including expression of cytokines. Of great interest, many of these changes were seen specifically in male deletion mice, and not female deletion mice. In contrast, adulthood neuron knockdown had more subtle effects on behavior, mainly on depression-like behavior in males. In addition, neuronal knockdown leads to upregulation of genes associated with Hedgehog and Wnt/Beta-catenin pathways in the hippocampus specifically in males. In summary, CHD8 is particularly important for microglial function in adulthood and has cellular effects that are specific to males in C57BL6 mice.https://doi.org/10.1038/s41398-025-03468-3 |
| spellingShingle | Orly Weissberg Ram Harari Chizim Dogun Dmitriy Getselter Evan Elliott CHD8 adulthood microglial knockdown in C57BL6 mice induces behavioral, morphological, and transcriptional changes in a sex-dependent manner Translational Psychiatry |
| title | CHD8 adulthood microglial knockdown in C57BL6 mice induces behavioral, morphological, and transcriptional changes in a sex-dependent manner |
| title_full | CHD8 adulthood microglial knockdown in C57BL6 mice induces behavioral, morphological, and transcriptional changes in a sex-dependent manner |
| title_fullStr | CHD8 adulthood microglial knockdown in C57BL6 mice induces behavioral, morphological, and transcriptional changes in a sex-dependent manner |
| title_full_unstemmed | CHD8 adulthood microglial knockdown in C57BL6 mice induces behavioral, morphological, and transcriptional changes in a sex-dependent manner |
| title_short | CHD8 adulthood microglial knockdown in C57BL6 mice induces behavioral, morphological, and transcriptional changes in a sex-dependent manner |
| title_sort | chd8 adulthood microglial knockdown in c57bl6 mice induces behavioral morphological and transcriptional changes in a sex dependent manner |
| url | https://doi.org/10.1038/s41398-025-03468-3 |
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