Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: A neurodevelopmental animal model of schizophrenia
Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: A neurodevelopmental animal model of schizophrenia
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DOI：
10.1016/j.biopsych.2005.07.031
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发表时间：
2006-03-15
影响因子：
10.6
通讯作者：
Iyo, M
中科院分区：
文献类型：
--
作者：
Ozawa, K;Hashimoto, K;Iyo, M
背景：母亲病毒感染与精神分裂症风险增加有关。据推测，母体对病毒的免疫反应可能会影响胎儿大脑发育并导致精神分裂症。方法：为了模拟病毒感染，将合成的双链 RNA 聚核糖肌苷-聚核糖胞二酸 (poly I:C) 给予怀孕小鼠。对磷酸盐缓冲盐水 (PBS) 处理的母鼠 (PBS-小鼠) 和聚 I:C 处理的母鼠 (聚 L C-小鼠) 的后代进行行为评估 (趋触性、甲基苯丙胺 [MAP] 诱导的多动、新物体识别测试 [NORT])、感觉运动门控 (前脉冲抑制 [PPI]) 和多巴胺能功能的生化评估结果：在幼年小鼠中，poy I:C 小鼠和 PBS 小鼠之间没有发现差异。然而，在成年中，与 PBS 小鼠相比，Poly I:C 小鼠表现出趋动性减弱、MAP 诱导的 (2 mg/kg) 过度运动反应更大、PPI 缺陷和 NORT 认知障碍。亚慢性给予氯氮平 (5.0 mg/kg) 可改善成年 Poly I:C 小鼠的认知障碍，但不能改善氟哌啶醇 (0.1 mg/kg)。在成年 Poly I:C 小鼠纹状体中发现多巴胺 (DA) 周转增加，D-2 样受体（而非 D-1 样受体）的受体结合减少。结论：产前 Poly I:C 给药会导致后代成熟依赖性皮层下 DA 功能增加和认知障碍，表明精神分裂症的神经发育动物模型。
Background: Maternal viral infection is associated with increased risk for schizophrenia. It is hypothesized that the maternal immune response to viruses may influence fetal brain development and lead to schizophrenia.Methods: To mimic a viral infection, the synthetic double strand RNA polyriboinosinic-polyribocytidilic acid (poly I:C) was administered into pregnant mice. Behavioral evaluations (thigmotaxis, methamphetamine [MAP]-induced hyperactivity, novel-object recognition test [NORT]), sensorimotor gating (prepulse inhibition [PPI]), and biochemical evaluation of the dopaminergic function of the offspring of phospbate-buffered saline (PBS)-treated dams (PBS-mice) and that of poly I:C-treated dams (poly L C-mice) were examined.Results: In juveniles, no difference was found between the poy I:C-mice and PBS-mice. However, in adults, the poly I:C-mice exhibited attenuated thigmotaxis, greater response in MAP-induced (2 mg/kg) hyperlocomotion, deficits in PPI, and cognitive impairment in NORT compared with the PBS-mice. Cognitive impairment in the adult poly I:C-mice could be improved by subchronic administration of clozapine (5.0 mg/kg) but not haloperidol (.1 mg/kg). increased dopamine (DA) turnover and decreased receptor binding of D-2-like receptors, but not D-1-like receptors, in the striatum were found in adult poly I:C-mice.Conclusions: Prenatal poly I:C administration causes maturation-dependent increased subcortical DA function and cognitive impairment in the offspring, indicating a neurodevelopmental animal model of schizophrenia.