Mutation of the histone demethylase Gasc1 causes ASD-like symptoms in mice
Abstract Background Genomic analyses of psychiatric disorders, including autism spectrum disorder (ASD), have revealed many susceptibility genes, suggesting that such disorders may be caused by multiple factors. In this sense, it has long been a question whether there is an abnormal genetic status t...
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BMC
2025-07-01
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| Series: | Inflammation and Regeneration |
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| Online Access: | https://doi.org/10.1186/s41232-025-00374-5 |
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| author | Tetsushi Kagawa Yuhei Yamaguchi Yasuhiro Kokubu Genki Sudo Aoi Ebisawa Satoko Hattori Keizo Takao Kohtarou Konno Naomi Nakagata Takafumi Inoue Masahiko Watanabe Johji Inazawa Tsuyoshi Miyakawa Tetsuya Taga |
| author_facet | Tetsushi Kagawa Yuhei Yamaguchi Yasuhiro Kokubu Genki Sudo Aoi Ebisawa Satoko Hattori Keizo Takao Kohtarou Konno Naomi Nakagata Takafumi Inoue Masahiko Watanabe Johji Inazawa Tsuyoshi Miyakawa Tetsuya Taga |
| author_sort | Tetsushi Kagawa |
| collection | DOAJ |
| description | Abstract Background Genomic analyses of psychiatric disorders, including autism spectrum disorder (ASD), have revealed many susceptibility genes, suggesting that such disorders may be caused by multiple factors. In this sense, it has long been a question whether there is an abnormal genetic status that comprehensively explains the pathogenesis of neuropsychiatric disorders or a"promising upstream treatment target"that normalizes symptoms. Methods To address this question, we provide important clues with respect to GASC1 (JMJD2 C/KDM4 C), which is a histone demethylase that prominently targets trimethylated histone H3 at lysine 9 (H3 K9 me3). Gasc1 hypomorphic mutant mice were analyzed using molecular biological, biochemical, behavioral battery tests, histological, and electrophysiological techniques. Results Mice homozygous for a hypomorphic mutation in Gasc1 exhibited abnormal behaviors, including hyperactivity, stereotyped behaviors, and impaired learning and memory, which are reminiscent of those of human psychiatric disorders. Electrophysiological studies of hippocampal slices revealed decreased paired-pulse facilitation and enhanced long-term potentiation, suggesting synaptic dysfunction in the mutants. Increased dendritic spine density in CA1 neurons was also detected in the mutants. Intriguingly, genetic linkage studies of human ASD have mapped a susceptibility locus on chromosome 9p24.1, which contains 78 genes, including the GASC1 gene. Conclusion Taken together, our data suggest that histone demethylation plays a pivotal role in normal brain development and higher-order brain functions in both mice and humans. |
| format | Article |
| id | doaj-art-a37489e7e72e41368892f9d5a069accb |
| institution | Kabale University |
| issn | 1880-8190 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Inflammation and Regeneration |
| spelling | doaj-art-a37489e7e72e41368892f9d5a069accb2025-08-20T03:46:04ZengBMCInflammation and Regeneration1880-81902025-07-0145112010.1186/s41232-025-00374-5Mutation of the histone demethylase Gasc1 causes ASD-like symptoms in miceTetsushi Kagawa0Yuhei Yamaguchi1Yasuhiro Kokubu2Genki Sudo3Aoi Ebisawa4Satoko Hattori5Keizo Takao6Kohtarou Konno7Naomi Nakagata8Takafumi Inoue9Masahiko Watanabe10Johji Inazawa11Tsuyoshi Miyakawa12Tetsuya Taga13Department of Stem Cell Regulation, Medical Research Laboratory, Institute for Integrated Research, Institute of Science Tokyo (Formerly Tokyo Medical and Dental University)Division of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto UniversityDepartment of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU)Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU)Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU)Section of Behavior Patterns, Center for Genetic Analysis of Behavior, National Institute for Physiological SciencesSection of Behavior Patterns, Center for Genetic Analysis of Behavior, National Institute for Physiological SciencesDepartment of Anatomy, Faculty of Medicine, Hokkaido UniversityDivision of Reproductive Biotechnology and Innovation, Center for Animal Resources and Development (CARD), Institute of Resource Development and Analysis, Kumamoto UniversityDepartment of Life Science and Medical Bioscience, Laboratory for Neurophysiology, Waseda UniversityDepartment of Anatomy, Faculty of Medicine, Hokkaido UniversityDepartment of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU)Section of Behavior Patterns, Center for Genetic Analysis of Behavior, National Institute for Physiological SciencesDepartment of Stem Cell Regulation, Medical Research Laboratory, Institute for Integrated Research, Institute of Science Tokyo (Formerly Tokyo Medical and Dental University)Abstract Background Genomic analyses of psychiatric disorders, including autism spectrum disorder (ASD), have revealed many susceptibility genes, suggesting that such disorders may be caused by multiple factors. In this sense, it has long been a question whether there is an abnormal genetic status that comprehensively explains the pathogenesis of neuropsychiatric disorders or a"promising upstream treatment target"that normalizes symptoms. Methods To address this question, we provide important clues with respect to GASC1 (JMJD2 C/KDM4 C), which is a histone demethylase that prominently targets trimethylated histone H3 at lysine 9 (H3 K9 me3). Gasc1 hypomorphic mutant mice were analyzed using molecular biological, biochemical, behavioral battery tests, histological, and electrophysiological techniques. Results Mice homozygous for a hypomorphic mutation in Gasc1 exhibited abnormal behaviors, including hyperactivity, stereotyped behaviors, and impaired learning and memory, which are reminiscent of those of human psychiatric disorders. Electrophysiological studies of hippocampal slices revealed decreased paired-pulse facilitation and enhanced long-term potentiation, suggesting synaptic dysfunction in the mutants. Increased dendritic spine density in CA1 neurons was also detected in the mutants. Intriguingly, genetic linkage studies of human ASD have mapped a susceptibility locus on chromosome 9p24.1, which contains 78 genes, including the GASC1 gene. Conclusion Taken together, our data suggest that histone demethylation plays a pivotal role in normal brain development and higher-order brain functions in both mice and humans.https://doi.org/10.1186/s41232-025-00374-5Autism spectrum disordersHyperactivityEpigenomeHistone methylationGASC1KDM4 C |
| spellingShingle | Tetsushi Kagawa Yuhei Yamaguchi Yasuhiro Kokubu Genki Sudo Aoi Ebisawa Satoko Hattori Keizo Takao Kohtarou Konno Naomi Nakagata Takafumi Inoue Masahiko Watanabe Johji Inazawa Tsuyoshi Miyakawa Tetsuya Taga Mutation of the histone demethylase Gasc1 causes ASD-like symptoms in mice Inflammation and Regeneration Autism spectrum disorders Hyperactivity Epigenome Histone methylation GASC1 KDM4 C |
| title | Mutation of the histone demethylase Gasc1 causes ASD-like symptoms in mice |
| title_full | Mutation of the histone demethylase Gasc1 causes ASD-like symptoms in mice |
| title_fullStr | Mutation of the histone demethylase Gasc1 causes ASD-like symptoms in mice |
| title_full_unstemmed | Mutation of the histone demethylase Gasc1 causes ASD-like symptoms in mice |
| title_short | Mutation of the histone demethylase Gasc1 causes ASD-like symptoms in mice |
| title_sort | mutation of the histone demethylase gasc1 causes asd like symptoms in mice |
| topic | Autism spectrum disorders Hyperactivity Epigenome Histone methylation GASC1 KDM4 C |
| url | https://doi.org/10.1186/s41232-025-00374-5 |
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