Maternal immune activation (MIA) increases risk for neuropsychiatric disorders such as autism spectrum disorder (ASD) in offspring later in life through unknown causal mechanisms. Growing evidence implicates parvalbumin-containing GABAergic interneurons as a key target in rodent MIA models. We targeted a specific neurodevelopmental window of parvalbumin interneurons in a mouse MIA model to examine effects on spatial working memory, a key domain in ASD that can manifest as either impairments and improvements both clinically and in animal models. Pregnant dams received three consecutive intraperitoneal injections of Polyinosinic:polycytidylic acid (poly(I:C), 5mg/kg) at gestational days 13, 14 and 15. Spatial working memory was assessed in young adult offspring using touchscreen operant chambers and the Trial-Unique Non-matching to Location (TUNL) task. Anxiety, novelty seeking and short-term memory were assessed using Elevated Plus Maze (EPM) and Y-maze novelty preference tasks. Fluorescent immunohistochemistry was used to assess hippocampal parvalbumin cell density, intensity and co-expression with perineuronal nets. qPCR was used to assess the expression of putatively implicated gene pathways. MIA targeting a window of parvalbumin interneuron development increased spatial working memory performance on the TUNL touchscreen task which was not influenced by anxiety or novelty seeking behaviour. The model reduced fetal mRNA levels of Gad1 and adult hippocampal mRNA levels of Pvalb and the distribution of low intensity parvalbumin interneurons was altered. We speculate a specific timing window for parvalbumin interneuron development underpins the apparently paradoxical improved spatial working memory phenotype found both across several rodent models of autism and clinically in ASD.

中文翻译：

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针对小清蛋白中间神经元发育窗口的母体免疫激活改善空间工作记忆：对自闭症的影响

母体免疫激活 (MIA) 会通过未知的因果机制增加后代患自闭症谱系障碍 (ASD) 等神经精神疾病的风险。越来越多的证据表明含有小清蛋白的 GABA 能中间神经元是啮齿动物 MIA 模型中的关键目标。我们针对小鼠 MIA 模型中小清蛋白中间神经元的特定神经发育窗口，以检查对空间工作记忆的影响，空间工作记忆是 ASD 的一个关键领域，可在临床和动物模型中表现为损伤和改善。怀孕的母猪在妊娠第 13、14 和 15 天接受连续三次腹膜内注射聚肌苷酸：聚胞苷酸（poly(I:C)，5mg/kg）。使用触摸屏操作室和 Trial-Unique Non-matching to Location (TUNL) 任务评估年轻成年后代的空间工作记忆。使用 Elevated Plus Maze (EPM) 和 Y 迷宫新奇偏好任务评估焦虑、新奇寻求和短期记忆。荧光免疫组织化学用于评估海马小清蛋白细胞密度、强度和与神经周围网的共表达。qPCR 用于评估假定涉及的基因途径的表达。针对小白蛋白中间神经元发育窗口的 MIA 增加了 TUNL 触摸屏任务的空间工作记忆性能，该任务不受焦虑或新奇寻求行为的影响。该模型降低了 Gad1 的胎儿 mRNA 水平和 Pvalb 的成人海马 mRNA 水平，并且低强度小清蛋白中间神经元的分布发生了改变。我们推测小清蛋白中间神经元发育的特定时间窗口支持在几种啮齿动物自闭症模型和临床 ASD 中发现的明显矛盾的改进空间工作记忆表型。