Department of Anatomy, Lake Erie College of Osteopathic Medicine, 1858 West Grandview Blvd, Erie, PA, 16504, USA.
Exp Brain Res. 2021 Feb;239(2):381-400. doi: 10.1007/s00221-020-05982-w. Epub 2020 Nov 16.
Auditory dysfunction, including hypersensitivity and tinnitus, is a common symptom of autism spectrum disorder (ASD). Prenatal exposure to the antiseizure medication valproic acid (VPA) significantly increases the risk of ASD in humans and similar exposure is utilized as an animal model of ASD in rodents. Animals exposed to VPA in utero have abnormal activity in their auditory cortex in response to sounds, fewer neurons, abnormal neuronal morphology, reduced expression of calcium-binding proteins, and reduced ascending projections to the central nucleus of the inferior colliculus. Unfortunately, these previous studies of central auditory circuits neglect the medial geniculate (MG), which serves as an important auditory relay from the midbrain to the auditory cortex. Here, we examine the structure and connectivity of the medial geniculate (MG) in rats prenatally exposed to VPA. Our results indicate that VPA exposure results in significantly smaller and fewer neurons in the ventral and medial nuclei of the MG. Furthermore, injections of the retrograde tract tracer fluorogold (FG) in the MG result in significantly fewer FG+ neurons in the inferior colliculus, superior olivary complex, and ventral cochlear nucleus. Together, we interpret these findings to indicate that VPA exposure results in hypoplasia throughout the auditory circuits and that VPA has a differential impact on some long-range axonal projections from brainstem centers to the thalamus. Together, our findings support the widespread impact of VPA on neurons and sensory circuits in the developing brain.
听觉功能障碍，包括过敏和耳鸣，是自闭症谱系障碍（ASD）的常见症状。产前暴露于抗癫痫药物丙戊酸（VPA）会显著增加人类患 ASD 的风险，类似的暴露被用于啮齿动物的 ASD 动物模型。在子宫内暴露于 VPA 的动物在对声音的反应中表现出听觉皮层活动异常、神经元减少、神经元形态异常、钙结合蛋白表达减少以及向中脑下丘中央核的上行投射减少。不幸的是，这些先前对中枢听觉回路的研究忽略了内侧膝状体（MG），它是从中脑到听觉皮层的重要听觉中继。在这里，我们研究了产前暴露于 VPA 的大鼠内侧膝状体（MG）的结构和连接。我们的结果表明，VPA 暴露导致 MG 的腹侧和内侧核中的神经元数量明显减少。此外，在 MG 中注射逆行示踪剂荧光金（FG）导致下丘、上橄榄复合体和耳蜗腹核中的 FG+神经元数量明显减少。总之，我们认为这些发现表明 VPA 暴露导致整个听觉回路的发育不良，并且 VPA 对来自脑干中心到丘脑的某些长程轴突投射具有不同的影响。总之，我们的研究结果支持 VPA 对发育中大脑中的神经元和感觉回路的广泛影响。
