Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester M13 9PT, United Kingdom.
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, 5 Cutcombe Road, London SE5 9RT, United Kingdom; King's College London, MRC Centre for Neurodevelopmental Disorders, New Hunt's House, Guy's Hospital Campus, London SE1 1UL, United Kingdom.
Brain Behav Immun. 2019 Jan;75:48-59. doi: 10.1016/j.bbi.2018.09.005. Epub 2018 Sep 12.
Maternal immune activation (mIA) in rodents is rapidly emerging as a key model for neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. Here, we optimise a mIA model in rats, aiming to address certain limitations of current work in this field. Specifically, the lack of clear evidence for methodology chosen, identification of successful induction of mIA in the dams and investigation of male offspring only. We focus on gestational and early juvenile changes in offspring following mIA, as detailed information on these critical early developmental time points is sparse. Following strain (Wistar, Lister Hooded, Sprague Dawley) comparison and selection, and polyriboinosinic-polyribocytidylic acid (poly I:C) dose selection (2.5-15 mg/kg single or once daily for 5 days), mIA was induced in pregnant Wistar rats with 10 mg/kg poly I:C i.p. on gestational day (GD) 15. Early morphometric analysis was conducted in male and female offspring at GD21 and postnatal day (PD) 21, eight dams for each treatment at each time point were used, 32 in total. Subsequent microglia analysis was conducted at PD21 in a small group of offspring. Poly I:C at 10 mg/kg i.p. induced a robust, but variable, plasma IL-6 response 3 h post-injection and reduced body weight at 6 h and 24 h post-injection in two separate cohorts of Wistar rats at GD15. Plasma IL-6 was not elevated at PD21 in offspring or dams. Poly I:C-induced mIA did not affect litter numbers, but resulted in PD21 pup, and GD21 placenta growth restriction. Poly I:C significantly increased microglial activation at PD21 in male hippocampi. We have identified 10 mg/kg poly I:C i.p on GD15 as a robust experimental approach for inducing mIA in Wistar rats and used this to identify early neurodevelopmental changes. This work provides a framework to study the developmental trajectory of disease-relevant, sex-specific phenotypic changes in rats.
母体免疫激活（mIA）在啮齿动物中迅速成为神经发育障碍（如自闭症谱系障碍[ASD]和精神分裂症）的关键模型。在这里，我们优化了一种大鼠 mIA 模型，旨在解决该领域当前工作的某些局限性。具体来说，缺乏对所选方法的明确证据，无法确定母体 mIA 的成功诱导，并且仅研究雄性后代。我们关注 mIA 后后代在妊娠期和幼年早期的变化，因为这些关键的早期发育时间点的详细信息很少。在进行了品系（Wistar、Lister Hooded、Sprague Dawley）比较和选择，以及聚肌胞苷酸（poly I:C）剂量选择（2.5-15mg/kg 单次或每日 1 次，连续 5 天）后，我们用 10mg/kg poly I:C 腹腔注射（i.p.）在妊娠第 15 天（GD）诱导怀孕 Wistar 大鼠发生 mIA。在 GD21 和产后第 21 天（PD21）对雄性和雌性后代进行早期形态计量学分析，每个时间点使用 8 只母鼠进行每种处理，总共 32 只。随后在一小部分后代中进行了小胶质细胞分析。在 GD15 的两个单独的 Wistar 大鼠队列中，10mg/kg i.p.的 poly I:C 诱导了强烈但可变的血浆 IL-6 反应，在注射后 3 小时，并在注射后 6 小时和 24 小时降低了体重。在后代或母鼠的 PD21 中，血浆 IL-6 没有升高。poly I:C 诱导的 mIA 并不影响产仔数，但导致 PD21 幼仔和 GD21 胎盘生长受限。poly I:C 显著增加了雄性海马中的小胶质细胞激活在 PD21。我们确定了 10mg/kg i.p.的 poly I:C 在 GD15 是诱导 Wistar 大鼠 mIA 的一种强大的实验方法，并使用该方法确定了早期神经发育变化。这项工作为研究与疾病相关的、具有性别特异性表型变化的大鼠发育轨迹提供了一个框架。
