Prenatal valproic acid (VPA) exposure is a well-known animal model of autism spectrum disorder (ASD) that produces alterations in embryonic and adult neurogenesis as well as adolescent/adulthood neurobehavioral phenotypes. However, the effects of prenatal VPA exposure on neural network excitability, especially during the synaptogenic period around eye opening, are not fully understood. In this study, we orally administered VPA (300 mg/kg) to pregnant Wistar rats on gestation day 15 and subsequently performed field potential recording in the CA1 area of hippocampal slices obtained from control (saline-exposed) and VPA-exposed rat pups between postnatal day (PND) 13 and PND18. In control slices, we observed an abrupt enhancement of stimulation-dependent responses including population spike (PS) amplitudes and field excitatory postsynaptic potential (fEPSP) slopes at PND16, which coincided with the average day of eye opening. In contrast, VPA-exposed pups exhibited delayed eye opening (PND17) and gradual rather than abrupt increases in PS amplitudes and fEPSP slopes over the duration of the synaptogenic period. We next investigated the involvement of ambient GABA (γ-aminobutyric acid) in PS generation using bicuculline methiodide (BMI), a GABA type A (GABA_A) receptor antagonist. In control slices, BMI enhanced PS amplitudes during PND14–15 (before eye opening) and had little effect thereafter during PND16–17; a subsequent regression model analysis of BMI ratios (the ratio of PS amplitudes in the presence and absence of BMI) indicated a possible developmental change between these periods. In contrast, almost identical regression models were obtained for BMI ratios during PND14–15 and PND16–17 in the VPA-exposed group, indicating the absence of a developmental change. Our results suggest that prenatal VPA exposure accelerates the development of hippocampal excitability before eye opening. Moreover, our experimental model can be used as a novel approach for the evaluation of developmental neurotoxicity.

产前丙戊酸（VPA）暴露是自闭症谱系障碍（ASD）的著名动物模型，它会引起胚胎和成人神经发生以及青少年/成人神经行为表型的改变。但是，尚未完全了解产前VPA暴露对神经网络兴奋性的影响，尤其是在睁眼周围的突触形成时期。在这项研究中，我们在妊娠第15天给怀孕的Wistar大鼠口服VPA（300 mg / kg），随后在从对照（盐水暴露）和VPA暴露的幼鼠之间获取的海马切片CA1区域进行了场电位记录产后一天（PND）13和PND18。在控制片中 我们观察到刺激依赖性反应的突然增强，包括PND16处的种群尖峰（PS）幅度和场兴奋性突触后突触电位（fEPSP）斜率，这与平均睁眼的时间相吻合。相比之下，暴露于VPA的幼崽在突触形成期间持续睁眼（PND17），并且PS振幅和fEPSP斜率逐渐而不是突然增加。接下来，我们研究了使用双甲硫脲（BMI），GABA A型（GABA）在周围的GABA（γ-氨基丁酸）参与PS生成的过程。_A）受体拮抗剂。在对照切片中，BMI增强了PND14-15期间（睁眼之前）的PS振幅，此后在PND16-17期间几乎没有影响。随后的BMI比率（存在和不存在BMI时PS振幅之比）的回归模型分析表明，这两个时期之间可能存在发育变化。相反，在暴露于VPA的人群中，PND14-15和PND16-17期间的BMI比率获得了几乎相同的回归模型，表明没有发育变化。我们的结果表明，产前VPA暴露可在睁眼之前加速海马兴奋性的发展。此外，我们的实验模型可以用作评估发育性神经毒性的新方法。