Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, 123 Tianfei Alley, Mochou Road, Nanjing 210004, PR China; Institute of Pediatrics, Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, PR China.
Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, 123 Tianfei Alley, Mochou Road, Nanjing 210004, PR China.
Neurotoxicology. 2022 Jul;91:155-165. doi: 10.1016/j.neuro.2022.05.008. Epub 2022 May 17.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive stereotyped behaviors. Prenatal exposure to the anticonvulsant drug valproic acid (VPA) is reported to induce ASD in human and ASD-like phenotypes in rodents. Unfortunately, the etiology and pathogenesis of ASD remains unclear.
Pregnant rats received an intraperitoneal injection of 600 mg/kg VPA on E12.5 to construct the ASD rat model in offspring. The different expression of long non-coding RNA (lncRNA) and mRNA profiles in the hippocampus were determined by RNA sequencing to investigate potential mechanisms of VPA-induced ASD. Gene Ontology (GO) and pathway enrichment analysis were performed to predict the function of dysregulated lncRNAs. Co-expression network and real-time polymerase chain reaction (RT-PCR) analysis were conducted to validate the potential regulatory lncRNA-mRNA network.
VPA increased the total distance, time spent in the central zone and self-grooming (open field test) in rats. Meanwhile, VPA induced social impairment (three-chamber sociability test) and repetitive behaviors (marble burying test). A total of 238 lncRNAs and 354 mRNAs were differentially expressed in the VPA group. In addition, the dysregulated lncRNAs were involved in neural function and developmental processes of ASD. 5 lncRNAs and 7 mRNAs were differently expressed and included in the lncRNA-mRNA co-expression network. RT-PCR confirmed the upregulation of 4 lncRNAs and 6 mRNAs, and identified a potential regulatory network of NONRATT021475.2 (lncRNA) and Desert hedgehog (Dhh). Moreover, VPA decreased the serum vitamin A (VA) levels in offspring rats on postnatal day (PND) 21 and 49. Importantly, VA supplementation significantly restored VPA-induced autism-related behaviors and upregulation of NONRATT021475.2 and Dhh in the hippocampus of ASD rats.
This study not only contributed to understand the importance of lncRNAs and mRNAs in the progression of ASD, but also identified VA as a potential therapy for the condition.
The data that support the findings of this study are available from the corresponding author with reasonable request.
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征是社交缺陷和重复刻板行为。据报道，产前暴露于抗惊厥药物丙戊酸（VPA）会在人类中引起 ASD，并在啮齿动物中引起 ASD 样表型。不幸的是，ASD 的病因和发病机制仍不清楚。
妊娠大鼠在 E12.5 时腹腔注射 600mg/kg VPA，构建后代 ASD 大鼠模型。通过 RNA 测序检测海马中长链非编码 RNA（lncRNA）和 mRNA 谱的差异表达，以探讨 VPA 诱导 ASD 的潜在机制。进行基因本体论（GO）和通路富集分析，以预测失调 lncRNA 的功能。进行共表达网络和实时聚合酶链反应（RT-PCR）分析，以验证潜在的调控 lncRNA-mRNA 网络。
VPA 增加了大鼠的总距离、中央区停留时间和自我修饰（旷场试验）。同时，VPA 诱导社会障碍（三箱社交性测试）和重复行为（埋珠试验）。VPA 组共有 238 个 lncRNA 和 354 个 mRNA 差异表达。此外，失调的 lncRNA 参与了 ASD 的神经功能和发育过程。5 个 lncRNA 和 7 个 mRNA 差异表达并包含在 lncRNA-mRNA 共表达网络中。RT-PCR 证实了 4 个 lncRNA 和 6 个 mRNA 的上调，并确定了 NONRATT021475.2（lncRNA）和 Desert hedgehog（Dhh）的潜在调控网络。此外，VPA 降低了后代大鼠在出生后第 21 天和第 49 天的血清维生素 A（VA）水平。重要的是，VA 补充显著恢复了 VPA 诱导的自闭症相关行为，并上调了 ASD 大鼠海马中的 NONRATT021475.2 和 Dhh。
本研究不仅有助于了解 lncRNA 和 mRNA 在 ASD 进展中的重要性，还确定了 VA 作为 ASD 潜在治疗方法的地位。
支持本研究结果的数据可向通讯作者索取，合理要求即可。
