Li Maolin, Qiao Zhifei, Li Jizheng, Zhou Hongli, Huang Dong, Cai Yan, Li Xiaolong, Zhang Zuo, Zhou Jianyun, Zhou Jiyin
Clinical Medical Research Center, The Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
Department of Orthopedics, First Clinical Medical College of Yunnan University of Traditional Chinese Medicine, Kunming, China.
Transl Psychiatry. 2025 Aug 7;15(1):271. doi: 10.1038/s41398-025-03450-z.
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.
The cumulative effects of GDM and prenatal VPA on both autistic behavior and dysmyelination in progeny have been investigated in this study.
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.
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.
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.
妊娠期糖尿病（GDM）和产前接触丙戊酸（VPA）均为后代患自闭症的危险因素。值得注意的是，胼胝体的髓鞘形成异常是连接GDM和自闭症白质病变的一个突出因素。
本研究探讨了GDM和产前VPA对后代自闭症行为和髓鞘形成异常的累积影响。
在体内，利用表现出瘦素受体缺陷并维持高脂饮食的雌性小鼠建立GDM模型，并对其进行产前VPA给药。在体外，在高脂高糖培养条件下用VPA处理少突胶质前体细胞（OPC）。
同时受到GDM和产前VPA影响的后代在社交互动、髓鞘形成和OPC成熟方面表现出类似仅暴露于VPA的下降情况。值得注意的是，应用氯马斯汀有助于促进髓鞘再生、改善自闭症行为并促进OPC的进展。此外，发现与单独由VPA引起的情况相比，GDM和产前VPA联合引起的髓鞘形成受损和OPC成熟障碍较轻。这种差异影响可归因于GDM和VPA对OPC中γ-氨基丁酸受体激活、OPC中细胞外调节蛋白激酶（ERK）磷酸化以及组蛋白脱乙酰酶3和双特异性磷酸酶5表达调节的相反影响。
我们描述了GDM和产前VPA对胎儿OPC中ERK磷酸化的拮抗作用，从而改变其增殖和分化，最终导致较轻的髓鞘形成异常和自闭症行为。
