Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology (ETH) Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
Brain Behav Immun. 2011 Oct;25(7):1316-21. doi: 10.1016/j.bbi.2011.06.012. Epub 2011 Jun 24.
Inflammation-induced disruption of fetal neurodevelopmental processes has been linked to the precipitation of long-lasting behavioral abnormalities and associated neuropathology. Recent longitudinal investigations in prenatal immune activation models have revealed developmental correspondences between the ontogeny of specific dopaminergic neuropathology and the postnatal onset of distinct forms of dopamine-dependent functional abnormalities implicated in schizophrenia. Two examples of such developmental correspondences are increased expression of the orphan nuclear receptor Nurr1 (NR4A2) in ventral midbrain areas and disruption of prepulse inhibition of the acoustic startle reflex, with both the neuroanatomical and behavioral effects emerging only in adult but not pre-pubertal subjects exposed to prenatal maternal inflammation. In the present study, we tested the hypothesis that Nurr1 may be a critical molecular mediator of prepulse inhibition deficits induced by prenatal immune activation. To this end, we compared the effects of prenatal immune challenge on adult PPI in wild-type (wt) mice and mice with a heterozygous constitutive deletion of Nurr1 (Nurr1+/-) using a well established mouse model of maternal immune activation by exposure to the viral mimetic poly(I:C) (=polyriboinosinic-polyribocytidilic acid). We found that prenatal poly(I:C) treatment on gestation day 9 was similarly effective in disrupting prepulse inhibition in adult wt and Nurr1+/- mice. Prenatal poly(I:C) treatment also generally increased midbrain Nurr1-positive cells and counteracted the genetically driven Nurr1 deficit in the substantia nigra. Our data thus suggest that at least under the present experimental conditions, Nurr1 is not essential for the development of prepulse inhibition deficits induced by prenatal immune activation.
炎症引起的胎儿神经发育过程的破坏与长期行为异常和相关神经病理学的发生有关。最近在产前免疫激活模型中的纵向研究揭示了特定多巴胺能神经病理学的发生与涉及精神分裂症的不同形式的多巴胺依赖性功能异常的产后发病之间存在发育对应关系。这种发育对应关系的两个例子是腹侧中脑区域中孤儿核受体 Nurr1（NR4A2）的表达增加和听觉惊跳反射的前脉冲抑制中断，这两种神经解剖和行为效应仅出现在暴露于产前母体炎症的成年但非青春期前的动物中。在本研究中，我们测试了 Nurr1 是否可能是产前免疫激活引起的前脉冲抑制缺陷的关键分子介导物的假设。为此，我们比较了野生型（wt）小鼠和 Nurr1 杂合性组成型缺失（Nurr1+/-）小鼠在暴露于病毒模拟物聚肌胞苷酸（poly(I:C)=多聚肌苷酸-多聚胞苷酸）的母体免疫激活的小鼠模型中，产前免疫挑战对成年 PPI 的影响。我们发现，在妊娠第 9 天对母体进行 poly(I:C)处理，同样可以有效地破坏成年 wt 和 Nurr1+/-小鼠的前脉冲抑制。产前 poly(I:C)处理还普遍增加了中脑 Nurr1 阳性细胞，并抵消了黑质中遗传驱动的 Nurr1 缺乏。因此，我们的数据表明，至少在目前的实验条件下，Nurr1 对于产前免疫激活引起的前脉冲抑制缺陷的发展并非必需。
