Dorsey Susan G, Mocci Evelina, Lane Malcolm V, Krueger Bruce K
Department of Pain and Translational Symptom Science University of Maryland School of Nursing, Baltimore, MD, 21201, USA.
Institute for Genome Sciences University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Transl Psychiatry. 2024 Dec 4;14(1):482. doi: 10.1038/s41398-024-03179-1.
There is an increased incidence of autism among the children of women who take the anti-epileptic, mood-stabilizing drug, valproic acid (VPA) during pregnancy; moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNA-seq data obtained from E12.5 fetal mouse brains 3 hours after VPA administration to the pregnant dam revealed that VPA rapidly and significantly increased or decreased the expression of approximately 7,300 genes. No significant sex differences in VPA-induced gene expression were observed. Expression of 399 autism risk genes was significantly altered by VPA as was expression of 258 genes that have been reported to modulate fetal brain development but are not otherwise linked to autism. Expression of genes associated with intracellular signaling pathways, neurogenesis, and excitation-inhibition balance as well as synaptogenesis, neuronal fate determination, axon and dendritic development, neuroinflammation, circadian rhythms, and epigenetic modulation of gene expression was dysregulated by VPA. Notably, at least 40 genes that are known to regulate embryonic neurogenesis were dysregulated by VPA. The goal of this study was to identify mouse genes that are: (a) significantly up- or downregulated by VPA in the fetal brain and (b) associated with autism and/or known to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity and, consequently behavior, in the adult. The genes meeting these criteria provide potential targets for future hypothesis-driven studies to elucidate the proximal causes of errors in brain connectivity underlying neurodevelopmental disorders such as autism.
在孕期服用抗癫痫、情绪稳定药物丙戊酸（VPA）的女性所生育的孩子中，自闭症发病率有所上升；此外，子宫内接触VPA会在啮齿动物和非人类灵长类动物中引发类似自闭症的症状。对在怀孕母鼠给予VPA 3小时后从E12.5胎儿小鼠大脑获得的RNA测序数据进行分析发现，VPA迅速且显著地增加或减少了约7300个基因的表达。未观察到VPA诱导的基因表达存在显著的性别差异。399个自闭症风险基因的表达以及258个据报道可调节胎儿大脑发育但与自闭症无其他关联的基因的表达均因VPA而发生显著改变。与细胞内信号通路、神经发生、兴奋-抑制平衡以及突触形成、神经元命运决定、轴突和树突发育、神经炎症、昼夜节律和基因表达的表观遗传调控相关的基因表达因VPA而失调。值得注意的是，至少40个已知调节胚胎神经发生的基因因VPA而失调。本研究的目的是鉴定出：（a）在胎儿大脑中被VPA显著上调或下调且（b）与自闭症相关和/或已知在胚胎神经发育过程中起作用的小鼠基因，这些过程的扰动有可能改变大脑连接性并进而影响成年后的行为。符合这些标准的基因可为未来基于假设的研究提供潜在靶点，以阐明自闭症等神经发育障碍背后大脑连接错误的近端原因。
