Maternal influenza viral infection causes schizophrenia-like alterations of 5-HT₂A and mGlu₂ receptors in the adult offspring.
Maternal influenza viral infection causes schizophrenia-like alterations of 5-HT₂A and mGlu₂ receptors in the adult offspring.
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DOI：
10.1523/jneurosci.4230-10.2011
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发表时间：
2011-02-02
期刊：
影响因子：
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通讯作者：
González-Maeso J
中科院分区：
文献类型：
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作者：
Moreno JL;Kurita M;Holloway T;López J;Cadagan R;Martínez-Sobrido L;García-Sastre A;González-Maeso J
流行病学研究表明，母亲感染流感病毒会增加成年后代患精神分裂症的风险。5-羟色胺和谷氨酸系统被怀疑是精神分裂症的病因，也是抗精神病药物的作用机制。致幻剂，如裸盖菇素和美斯卡林，需要5-羟色胺5-HT 2A受体的作用，并诱导人类精神分裂症样精神病。此外，代谢型谷氨酸受体mGlu 2/3激动剂显示出作为精神分裂症的新治疗的希望。在这里，我们研究了5-HT 2A和mGlu 2受体在母体流感病毒感染的小鼠模型中的表达水平和行为功能。我们发现，自发运动活动减少了与小鼠适应的流感A/WSN/33（H1N1）病毒的母体感染。对致幻剂和谷氨酸抗精神病药的行为反应都受到母体暴露于流感病毒的影响，对致幻剂的头部抽搐反应增加，谷氨酸激动剂的抗精神病样作用减弱。在流感病毒感染的母亲所生小鼠的额叶皮层中，5-HT 2A受体上调，mGlu 2受体下调，这种改变可能与观察到的行为变化有关。此外，我们发现，皮质5-HT 2A受体依赖性信号通路显着改变，在后代的感染的母亲，表现出较高的c-fos，ESTA-1和ESTA-2的表达在致幻药物DOI的反应。确定一种与产前病毒感染小鼠模型中观察到的行为变化平行的生物化学改变，可能有助于治疗和预防精神分裂症的靶向治疗。
Epidemiological studies indicate that maternal influenza viral infection increases the risk for schizophrenia in the adult offspring. The serotonin and glutamate systems are suspected in the etiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. The effects of hallucinogens, such as psilocybin and mescaline, require the serotonin 5-HT2A receptor, and induce schizophrenia-like psychosis in humans. In addition, metabotropic glutamate receptor mGlu2/3 agonists show promise as a new treatment for schizophrenia. Here, we investigated the level of expression and behavioral function of 5-HT2A and mGlu2 receptors in a mouse model of maternal influenza viral infection. We show that spontaneous locomotor activity is diminished by maternal infection with the mouse-adapted influenza A/WSN/33 (H1N1) virus. The behavioral responses to hallucinogens and glutamate antipsychotics are both affected by maternal exposure to influenza virus, with increased head-twitch response to hallucinogens and diminished antipsychotic-like effect of the glutamate agonist. In frontal cortex of mice born to influenza virus-infected mothers, the 5-HT2A receptor is up-regulated and the mGlu2 receptor is down-regulated, an alteration that may be involved in the behavioral changes observed. Additionally, we find that the cortical 5-HT2A receptor-dependent signaling pathways are significantly altered in the offspring of infected mothers, showing higher c-fos, egr-1 and egr-2 expression in response to the hallucinogenic drug DOI. Identifying a biochemical alteration that parallels the behavioral changes observed in a mouse model of prenatal viral infection may facilitate targeting therapies for treatment and prevention of schizophrenia.