Gestational diabetes induces autistic-like behaviors in offspring by disrupting the GABAergic system
BackgroundIncreasing evidence have shown that gestational diabetes mellitus (GDM) is associated with the risk of autism in offspring. However, the underlying mechanisms have not yet been fully elucidated.MethodsA mouse model of gestational diabetes mellitus (GDM) was established to investigate its i...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2025.1538115/full |
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| author | Xuan-Qi Liu Tian-li Huang Shu-Yu Zhang Yu-Tong Huang Jia-Ying Mo Yi-Shang Yan Yi-Ning Cao Yue-Ran Cai Jian-Zhong Sheng Hong Zhu He Feng Huang |
| author_facet | Xuan-Qi Liu Tian-li Huang Shu-Yu Zhang Yu-Tong Huang Jia-Ying Mo Yi-Shang Yan Yi-Ning Cao Yue-Ran Cai Jian-Zhong Sheng Hong Zhu He Feng Huang |
| author_sort | Xuan-Qi Liu |
| collection | DOAJ |
| description | BackgroundIncreasing evidence have shown that gestational diabetes mellitus (GDM) is associated with the risk of autism in offspring. However, the underlying mechanisms have not yet been fully elucidated.MethodsA mouse model of gestational diabetes mellitus (GDM) was established to investigate its impact on offspring. Behavioral analyses were conducted to assess social novelty and stereotypic behaviors. Neuronal excitability in the prefrontal cortex (PFC) was evaluated using c-Fos staining after social behavior stimulation. Single-cell transcriptomics and metabolomics were employed to analyze changes in the GABAergic system.ResultsBehavioral analyses revealed that GDM led to impaired social novelty and increased stereotypic behaviors in male offspring. c-Fos staining showed hyperexcitability in the PFC of male offspring from the GDM group following social behavior stimulation. Single-cell transcriptomics and metabolomics identified alterations in the GABAergic system, including a decrease in GABAergic neurons and reduced GABA levels. This reduction in GABA was associated with decreased GAD2 expression due to DNA hypermethylation in the GAD2 promoter region.ConclusionThese data suggest that GDM induces autistic-like behaviors, including reduced social novelty and increased stereotypic behaviors, in offspring by affecting the GABAergic system. These findings provide new insights into how GDM may influence neurodevelopment in offspring. |
| format | Article |
| id | doaj-art-96908acd49964c88935b759abbce4788 |
| institution | Kabale University |
| issn | 1662-453X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj-art-96908acd49964c88935b759abbce47882025-02-12T07:26:33ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2025-02-011910.3389/fnins.2025.15381151538115Gestational diabetes induces autistic-like behaviors in offspring by disrupting the GABAergic systemXuan-Qi Liu0Tian-li Huang1Shu-Yu Zhang2Yu-Tong Huang3Jia-Ying Mo4Yi-Shang Yan5Yi-Ning Cao6Yue-Ran Cai7Jian-Zhong Sheng8Hong Zhu9He Feng Huang10The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Zhejiang University School of Medicine, Hangzhou, ChinaThe Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Zhejiang University School of Medicine, Hangzhou, ChinaThe International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaThe Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Zhejiang University School of Medicine, Hangzhou, ChinaKey Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaThe Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaThe Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Zhejiang University School of Medicine, Hangzhou, ChinaThe Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Zhejiang University School of Medicine, Hangzhou, ChinaThe Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Zhejiang University School of Medicine, Hangzhou, ChinaObstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, ChinaThe Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Zhejiang University School of Medicine, Hangzhou, ChinaBackgroundIncreasing evidence have shown that gestational diabetes mellitus (GDM) is associated with the risk of autism in offspring. However, the underlying mechanisms have not yet been fully elucidated.MethodsA mouse model of gestational diabetes mellitus (GDM) was established to investigate its impact on offspring. Behavioral analyses were conducted to assess social novelty and stereotypic behaviors. Neuronal excitability in the prefrontal cortex (PFC) was evaluated using c-Fos staining after social behavior stimulation. Single-cell transcriptomics and metabolomics were employed to analyze changes in the GABAergic system.ResultsBehavioral analyses revealed that GDM led to impaired social novelty and increased stereotypic behaviors in male offspring. c-Fos staining showed hyperexcitability in the PFC of male offspring from the GDM group following social behavior stimulation. Single-cell transcriptomics and metabolomics identified alterations in the GABAergic system, including a decrease in GABAergic neurons and reduced GABA levels. This reduction in GABA was associated with decreased GAD2 expression due to DNA hypermethylation in the GAD2 promoter region.ConclusionThese data suggest that GDM induces autistic-like behaviors, including reduced social novelty and increased stereotypic behaviors, in offspring by affecting the GABAergic system. These findings provide new insights into how GDM may influence neurodevelopment in offspring.https://www.frontiersin.org/articles/10.3389/fnins.2025.1538115/fullgestational diabetes (GDM)autismneurodevelopmentGABAbehavior |
| spellingShingle | Xuan-Qi Liu Tian-li Huang Shu-Yu Zhang Yu-Tong Huang Jia-Ying Mo Yi-Shang Yan Yi-Ning Cao Yue-Ran Cai Jian-Zhong Sheng Hong Zhu He Feng Huang Gestational diabetes induces autistic-like behaviors in offspring by disrupting the GABAergic system Frontiers in Neuroscience gestational diabetes (GDM) autism neurodevelopment GABA behavior |
| title | Gestational diabetes induces autistic-like behaviors in offspring by disrupting the GABAergic system |
| title_full | Gestational diabetes induces autistic-like behaviors in offspring by disrupting the GABAergic system |
| title_fullStr | Gestational diabetes induces autistic-like behaviors in offspring by disrupting the GABAergic system |
| title_full_unstemmed | Gestational diabetes induces autistic-like behaviors in offspring by disrupting the GABAergic system |
| title_short | Gestational diabetes induces autistic-like behaviors in offspring by disrupting the GABAergic system |
| title_sort | gestational diabetes induces autistic like behaviors in offspring by disrupting the gabaergic system |
| topic | gestational diabetes (GDM) autism neurodevelopment GABA behavior |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2025.1538115/full |
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