Ex vivo Electrophysiology Laboratory, Department of Physiology and Neurobiology, Institute of Biology, Eötvös Loránd University, Budapest, Hungary.
Front Neural Circuits. 2022 Feb 4;16:772792. doi: 10.3389/fncir.2022.772792. eCollection 2022.
Autism Spectrum Disorder (ASD) is one of the most frequently diagnosed neurodevelopmental disorders, characterized among others by impairments in social interactions and repetitive behavior. According to one of the leading hypotheses about its origin, ASD is caused by the imbalance of excitatory and inhibitory circuit activity. ASD-related morphological and functional changes can be observed in several brain regions i.e., in the prefrontal cortex and the hippocampus. It is well-established that prenatal valproic-acid (VPA) exposure of rats on day 12.5 leads to neurodevelopmental alterations with autism-like clinical and behavioral symptoms. The aim of this study was to investigate potential changes in the excitability of neuronal networks and individual neurons of the hippocampus elicited by prenatal VPA treatment. As there are marked sex differences in ASD, offspring of both sexes were systematically tested, using two different age groups, to elucidate eventual differences in neurodevelopment after VPA treatment. Excitatory connections and long-term synaptic plasticity as well as intrinsic excitability of CA1 pyramidal cells were examined. Pregnant female Wistar rats received saline or 500 mg/kg VPA i. p. on gestation day 12.5. Brain slices of 6-week-old and 3-month-old offspring were investigated using extra- and intracellular electrophysiological techniques. Field potential- and whole-cell patch clamp recordings were carried out to measure network excitability and single cell activity in the CA1 region hippocampus. Enhanced excitability of hippocampal networks was detected in the 6-week-old VPA-treated male rats; however, this change could not be observed in 3-month-old males. Intrinsic excitability of single neurons, however, was increased in 3-month-old males. In 6-week-old treated females, the most prominent effect of VPA was an increase in voltage sag, to a similar degree to the neurons of the older age group. In 3-month-old females, a network excitability increase could be demonstrated, in a lesser degree than in younger males. It can be concluded, that VPA treatment had diverse effects on hippocampal excitability depending on the sex and the age of the animals. We found that certain alterations manifested in 6-week-old rats were compensated later, on the other hand, other changes persisted until the age of 3 months.
自闭症谱系障碍（ASD）是最常见的神经发育障碍之一，其特征除其他外还包括社交互动和重复行为障碍。根据其起源的主要假设之一，ASD 是由兴奋性和抑制性电路活动失衡引起的。ASD 相关的形态和功能变化可在几个脑区观察到，例如前额叶皮层和海马体。众所周知，在妊娠第 12.5 天给大鼠使用丙戊酸（VPA）会导致具有自闭症样临床和行为症状的神经发育改变。本研究的目的是研究产前 VPA 处理对海马神经元网络和单个神经元兴奋性的潜在影响。由于 ASD 存在明显的性别差异，因此系统地测试了雄性和雌性后代，使用两个不同的年龄组来阐明 VPA 处理后神经发育的差异。研究了兴奋性连接和长时程突触可塑性以及 CA1 锥体神经元的内在兴奋性。妊娠雌性 Wistar 大鼠在妊娠第 12.5 天接受生理盐水或 500mg/kg VPA 腹膜内注射。使用细胞外和细胞内电生理技术研究 6 周龄和 3 月龄后代的脑切片。在 CA1 区海马体中进行场电位和全细胞膜片钳记录，以测量网络兴奋性和单个细胞活动。在 6 周龄 VPA 处理的雄性大鼠中检测到海马网络的兴奋性增强；然而，在 3 月龄雄性大鼠中未观察到这种变化。然而，3 月龄雄性的单个神经元的内在兴奋性增加。在 6 周龄的处理雌性中，VPA 的最显著作用是电压凹陷增加，与较年长组的神经元相似。在 3 月龄的雌性中，在较小程度上可以证明网络兴奋性增加。可以得出结论，VPA 处理对海马体兴奋性的影响因动物的性别和年龄而异。我们发现，某些在 6 周龄大鼠中表现出的改变在后期得到了代偿，另一方面，其他改变持续到 3 月龄。
