Chronic Toxoplasma gondii in Nurr1-null heterozygous mice exacerbates elevated open field activity.
Chronic Toxoplasma gondii in Nurr1-null heterozygous mice exacerbates elevated open field activity.
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DOI：
10.1371/journal.pone.0119280
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lindsay DS
中科院分区：
文献类型：
--
作者：
Eells JB;Varela-Stokes A;Guo-Ross SX;Kummari E;Smith HM;Cox AD;Lindsay DS
弓形虫潜伏感染在人类中很常见(约占全球人口的30%)，是精神分裂症的一个重要风险因素。由于弓形虫感染的患病率远远高于精神分裂症的患病率(0.5%-1%)，遗传风险因素可能也是导致精神分裂症的必要因素。为了在动物模型中验证这一概念，对Nurr1缺失杂合子(+/-)小鼠和野生型(+/+)小鼠进行了涌现试验、在野外和新对象中的活动、在感染弓形虫前和感染后6周对山猫尿液的反应和对声学惊厥反应(PPI)的预脉冲抑制。在出现试验中，弓形虫感染显著减少了在圆筒中停留的时间。弓形虫感染显著增加了+/+和+/-小鼠的野外活动，但这种增加在+/-小鼠中显着加剧。弓形虫感染降低了雄性+/-小鼠的PPI，但这在统计学上没有显着意义。弓形虫感染可消除+/+小鼠对山猫尿液的厌恶。雌性+/-小鼠感染弓形虫后仍对山猫尿液产生厌恶，而雄性+/-小鼠对山猫尿液不产生厌恶。感染小鼠的抗体效价是与野外活动变化相关的关键变量，即抗体滴度与野外活动的百分比变化之间存在倒U型关系，在低抗体滴度和中等抗体滴度时活性显著增加，而在高抗体滴度时则没有影响。这些数据表明，Nurr1+/-基因型使小鼠容易受到弓形虫诱导的行为变化的影响，这些行为涉及多巴胺神经传递，并与精神分裂症的症状有关。我们推测，小鼠行为的这些改变是由于Nurr1+/-小鼠中改变的多巴胺神经传递的进一步加剧。
Latent infection with Toxoplasma gondii is common in humans (approximately 30% of the global population) and is a significant risk factor for schizophrenia. Since prevalence of T. gondii infection is far greater than prevalence of schizophrenia (0.5-1%), genetic risk factors are likely also necessary to contribute to schizophrenia. To test this concept in an animal model, Nurr1-null heterozygous (+/-) mice and wild-type (+/+) mice were evaluate using an emergence test, activity in an open field and with a novel object, response to bobcat urine and prepulse inhibition of the acoustic startle response (PPI) prior to and 6 weeks after infection with T. gondii. In the emergence test, T. gondii infection significantly decreased the amount of time spent in the cylinder. Toxoplasma gondii infection significantly elevated open field activity in both +/+ and +/- mice but this increase was significantly exacerbated in +/- mice. T. gondii infection reduced PPI in male +/- mice but this was not statistically significant. Aversion to bobcat urine was abolished by T. gondii infection in +/+ mice. In female +/- mice, aversion to bobcat urine remained after T. gondii infection while the male +/- mice showed no aversion to bobcat urine. Antibody titers of infected mice were a critical variable associated with changes in open field activity, such that an inverted U shaped relationship existed between antibody titers and the percent change in open field activity with a significant increase in activity at low and medium antibody titers but no effect at high antibody titers. These data demonstrate that the Nurr1 +/- genotype predisposes mice to T. gondii-induced alterations in behaviors that involve dopamine neurotransmission and are associated with symptoms of schizophrenia. We propose that these alterations in murine behavior were due to further exacerbation of the altered dopamine neurotransmission in Nurr1 +/- mice.
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