Most animal model studies of autism spectrum disorder (ASD) have been performed in males, which may be a reflex of the 3-times higher prevalence in boys than in girls. For this reason, little is known about the mechanisms underlying disease progression in females, and nothing is known about potential associations between microglial changes in the lateral septum (LS) and adult female cognition. Prenatal exposure to valproic acid (VPA) in mice has been widely used as an experimental model of autism-like behaviors associated with cellular changes. However, no study has reported the influence of VPA exposure in utero and its consequences on limbic system-dependent tasks or the microglial response in the LS in adult female mice. We compared the exploratory activity and risk assessment in novel environments of BALB/c control mice to mice exposed in utero to VPA and estimated the total number of microglia in the LS using an optical fractionator. On day 12.5 of pregnancy, females received diluted VPA or saline by gavage. After weaning, VPA exposed or control pups were separately housed in standard laboratory cages. At 5 months of age, all mice underwent behavioral testing and their brain sections were immunolabelled using IBA-1 antibody. In the open field test, VPA group showed a greater distance traveled, which was accompanied by less immobility, less time spent on the periphery and a greater number, crossed lines. Similar findings were found in the elevated plus maze test, where VPA mice traveled greater distances, immobility was significantly higher than that of control and VPA group spent less time on the closed arms of apparatus. Stereological analysis demonstrated higher microglial total number and density in the LS of VPA mice, as the cell count was greater, but the volume was similar. Therefore, we suggest that an increase in microglia in the LS may be part of the cellular changes associated with behavioral dysfunction in the VPA model of ASD.

中文翻译：

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产前暴露于丙戊酸的小鼠侧隔小胶质细胞变化和行为异常

大多数自闭症谱系障碍 (ASD) 的动物模型研究都是在男性中进行的，这可能反映了男孩的患病率是女孩的 3 倍。出于这个原因，对女性疾病进展的潜在机制知之甚少，并且对侧隔 (LS) 中的小胶质细胞变化与成年女性认知之间的潜在关联一无所知。小鼠产前暴露于丙戊酸 (VPA) 已被广泛用作与细胞变化相关的自闭症样行为的实验模型。然而，没有研究报告子宫内 VPA 暴露的影响及其对边缘系统依赖任务或成年雌性小鼠 LS 中小胶质细胞反应的影响。我们比较了 BALB/c 对照小鼠与在子宫内暴露于 VPA 的小鼠在新环境中的探索活动和风险评估，并使用光学分馏器估计了 LS 中小胶质细胞的总数。在怀孕的第 12.5 天，雌性通过管饲法接受稀释的 VPA 或生理盐水。断奶后，暴露于 VPA 的幼崽或对照幼崽分别饲养在标准实验室笼子中。在 5 个月大时，所有小鼠都接受了行为测试，并使用 IBA-1 抗体对它们的大脑切片进行了免疫标记。在野外测试中，VPA 组表现出更远的行进距离，伴随着更少的不动、更少的时间在外围以及更多的交叉线。在高架十字迷宫测试中也发现了类似的发现，其中 VPA 小鼠移动了更远的距离，静止性显着高于对照组，VPA组在器械闭合臂上花费的时间更少。体视学分析表明，VPA 小鼠 LS 中的小胶质细胞总数和密度更高，因为细胞计数更大，但体积相似。因此，我们认为 LS 中小胶质细胞的增加可能是 ASD 的 VPA 模型中与行为功能障碍相关的细胞变化的一部分。