Prenatal valproic acid on the basis of gestational diabetes also induces autistic behavior and disrupts myelination and oligodendroglial maturation slightly in offspring
Abstract Introduction Gestational diabetes mellitus (GDM) and prenatal exposure to valproic acid (VPA) are both constitute risk factors for autism in progeny. Notably, dysmyelination in the corpus callosum serves as a prominent element connecting GDM and autism in the white matter lesions. Objective...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-08-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03450-z |
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| Summary: | Abstract Introduction Gestational diabetes mellitus (GDM) and prenatal exposure to valproic acid (VPA) are both constitute risk factors for autism in progeny. Notably, dysmyelination in the corpus callosum serves as a prominent element connecting GDM and autism in the white matter lesions. Objective The cumulative effects of GDM and prenatal VPA on both autistic behavior and dysmyelination in progeny have been investigated in this study. Methods In vivo, female mice exhibiting leptin receptor deficiencies and maintained on a high-fat diet were utilized to create GDM models, to which prenatal VPA was administered. In vitro, oligodendrocyte precursor cells (OPCs) were treated with VPA in the high-fat and high-glucose culture. Results The offspring subjected to both GDM and prenatal VPA demonstrated comparable declines in social interaction, myelination, and OPC maturation, akin to those exclusively exposed to VPA. Remarkably, the application of clemastine facilitated remyelination, ameliorated autistic behaviors, and promoted the progression of OPCs. Furthermore, the compromised myelination and OPC maturation instigated by the combination of GDM and prenatal VPA were found to be less severe compared to those precipitated by VPA alone. This differential impact can be attributed to the opposing influences of GDM and VPA on gamma-aminobutyric acid receptor activation in OPCs, extracellular regulated protein kinases (ERK) phosphorylation in OPCs, and the modulation of histone deacetylase 3 and dual specificity phosphatase 5 expression. Conclusions we delineate the antagonistic effects of GDM and prenatal VPA on ERK phosphorylation in fetal OPCs, consequently altering their proliferation and differentiation, thereby culminating in milder dysmyelination and autistic behaviors. |
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| ISSN: | 2158-3188 |