Abstract：
Exposing the immature nervous system to specific antiepileptic drugs (AEDs) during pregnancy is linked to neurodevelopmental disorders such as autism spectrum disorder (ASD). Newer AEDs like lamotrigine (LTG) are hailed as safer, but recent epidemiological data suggest that even LTG carries a risk, although much lower than that associated with valproic acid (VPA), an older AED, which is also known to cause morphological alterations in the developing brain. Increasing evidence highlights cerebellar abnormalities as important in ASD pathophysiology. Transcription factor PAX6 is a key activity-dependent mediator and regulates crucial processes during cerebellar development. The chicken cerebellum recapitulates important characteristics of human cerebellar development, and may thus be suitable for the assessment of interventions aiming to modify maturation and cerebellar development. In the present study, exposure of chicken on embryonic day 16 (E16) to LTG or VPA resulted in decreased cerebellar mass and level of proliferating nuclear cell antigen (PCNA) for clinically relevant concentrations of VPA. However, both AEDs reduced cerebellar protein levels of PAX6 and MMP-9 at E17. Furthermore, PAX6 immunohistochemical staining of coronal sections of chicken cerebellum showed a significant reduction in PAX6-positive cell density and changes in cerebellar cortex thickness, mostly caused by the change in IGL-layer thickness. In conclusion, prenatal exposure to LTG or VPA provoked differential maturational changes in the developing cerebellum that may reflect some of the underlying molecular mechanisms for the observed human ASD pathology after AEDs exposure during pregnancy.
摘要：
在怀孕期间将未成熟的神经系统暴露于特定的抗癫痫药物（AED）与神经发育障碍有关，例如自闭症谱系障碍（ASD）。拉莫三嗪（LTG）等较新的AED被誉为更安全，但是最近的流行病学数据表明，即使是LTG也有风险，尽管远低于与丙戊酸（VPA）相关的水平，一个较旧的AED,这也被认为会导致发育中的大脑形态改变。越来越多的证据强调小脑异常在ASD病理生理学中很重要。转录因子PAX6是一种关键的活性依赖性介质，调节小脑发育过程中的关键过程。鸡小脑概括了人类小脑发育的重要特征，因此，可能适用于评估旨在改变成熟和小脑发育的干预措施。在本研究中,鸡在胚胎第16天（E16）暴露于LTG或VPA会导致小脑质量和临床相关VPA浓度的增殖核细胞抗原（PCNA）水平降低。然而,两种AED均降低了E17时小脑PAX6和MMP-9的蛋白水平。此外，鸡小脑冠状切片的PAX6免疫组织化学染色显示PAX6阳性细胞密度显著降低,小脑皮质厚度改变,主要由IGL层厚度的变化引起。总之,产前暴露于LTG或VPA会引起发育中小脑的不同成熟变化，这可能反映了妊娠期AEDs暴露后观察到的人类ASD病理的一些潜在分子机制。
