Department of Anatomy, Lake Erie College of Osteopathic Medicine, 1858 West Grandview Blvd, Erie, PA, 16504, USA.
Exp Brain Res. 2020 Mar;238(3):551-563. doi: 10.1007/s00221-020-05729-7. Epub 2020 Jan 25.
Prenatal exposure to the antiepileptic valproic acid (VPA) is associated with an increased risk of autism spectrum disorder (ASD) in humans. Accordingly, in utero exposure to VPA is a validated and biologically relevant animal model of ASD. The majority of individuals with ASD exhibit some degree of auditory dysfunction, ranging from deafness to hypersensitivity. Animals exposed to VPA in utero have abnormal tonotopic maps and responses in the cerebral cortex and hyperactivation, hypoplasia, abnormal neuronal morphology and reduced calcium binding protein expression throughout the auditory brainstem nuclei. Further, our previous work suggests that GABAergic neuronal populations may be more severely impacted by in utero VPA exposure. However, the axonal projection patterns of brainstem nuclei to the inferior colliculus (IC) have not been investigated in VPA-exposed animals. Herein, we use stereotaxic injections of the retrograde tracer Fast Blue into the central nucleus of the IC (CNIC) and examine the proportions of retrogradely labeled neurons in the nuclei of the lateral lemniscus, superior olivary complex and cochlear nuclei. Our results indicate that not only are there fewer neurons in the auditory brainstem after VPA exposure, but also that fewer neurons are retrogradely labeled from the CNIC. Together, our results indicate that in utero VPA exposure may result in altered patterns of input to the auditory midbrain.
产前暴露于抗癫痫药丙戊酸（VPA）与人类自闭症谱系障碍（ASD）的风险增加有关。因此，子宫内暴露于 VPA 是 ASD 的一种经过验证且具有生物学相关性的动物模型。大多数 ASD 患者都存在一定程度的听觉功能障碍，从耳聋到超敏反应不等。子宫内暴露于 VPA 的动物在大脑皮层中表现出异常的音调图谱和反应，以及听觉脑干核中的过度活跃、发育不良、异常神经元形态和减少钙结合蛋白表达。此外，我们之前的工作表明，GABA 能神经元群体可能更容易受到子宫内 VPA 暴露的影响。然而，尚未在 VPA 暴露的动物中研究脑干核到下丘（IC）的轴突投射模式。在此，我们使用逆行示踪剂 Fast Blue 对 IC 的中央核（CNIC）进行立体定向注射，并检查标记有逆行标记的神经元在外侧丘系核、上橄榄复合体和耳蜗核中的比例。我们的结果表明，VPA 暴露后不仅听觉脑干中的神经元数量减少，而且从 CNIC 逆行标记的神经元数量也减少。总之，我们的结果表明，子宫内 VPA 暴露可能导致听觉中脑输入模式的改变。
