Cui Ke, Ashdown Helen, Luheshi Giamal N, Boksa Patricia
Department of Psychiatry and of Neurology and Neurosurgery, McGill University, Douglas Mental Health University Institute, Montreal, Quebec, Canada.
Schizophr Res. 2009 Sep;113(2-3):288-97. doi: 10.1016/j.schres.2009.05.003. Epub 2009 May 22.
Maternal infection during pregnancy has been associated with an increased risk for the development of schizophrenia, a disorder characterized by abnormalities in hippocampal morphology and function. Neurogenesis occurs in the hippocampus throughout development into adulthood and is believed to modulate hippocampal function. This study used a rat model in which bacterial endotoxin, lipopolysaccharide (LPS), is administered to pregnant dams, to test if prenatal immune activation has acute and/or long term effects on various phases of neurogenesis (proliferation, survival, differentiation) in the hippocampal dentate gyrus of offspring. When LPS was administered to dams on gestation days (GD) 15 and 16, there was decreased proliferation of dentate cells at postnatal day (PD) 14 and decreased survival of cells generated at PD14 in offspring. When prenatal exposure to LPS was later in pregnancy (GD 18 and 19), offspring showed decreased survival of cells generated both at the time of LPS exposure and at PD14. There was no change in cell proliferation or survival in adult offspring at PD60, with prenatal LPS exposure. Co-administration of the cyclo-oxygenase inhibitor, ibuprofen (IBU), together with prenatal LPS on GD 15 and 16, was unable to prevent the deficit in neuronal survival at PD14. IBU blocked LPS-induced fever but did not block LPS-induced increases in plasma cytokines and corticosterone in the pregnant dam. This indicates that deficits in neurogenesis caused by prenatal LPS are not mediated by LPS-induced fever or eicosanoid induction, but could be mediated by LPS-induced increases in maternal cytokines or corticosterone.
孕期母体感染与精神分裂症发病风险增加有关，精神分裂症是一种以海马形态和功能异常为特征的疾病。神经发生在整个发育过程直至成年期都在海马中发生，并被认为可调节海马功能。本研究使用一种大鼠模型，即给怀孕的母鼠注射细菌内毒素脂多糖（LPS），以测试产前免疫激活对后代海马齿状回神经发生的各个阶段（增殖、存活、分化）是否有急性和/或长期影响。当在妊娠第15天和16天给母鼠注射LPS时，后代在出生后第14天齿状细胞的增殖减少，且出生后第14天产生的细胞存活率降低。当孕期较晚时（妊娠第18天和19天）产前暴露于LPS，后代在LPS暴露时和出生后第14天产生的细胞存活率均降低。产前暴露于LPS的成年后代在出生后第60天细胞增殖或存活没有变化。在妊娠第15天和16天，将环氧化酶抑制剂布洛芬（IBU）与产前LPS联合使用，无法预防出生后第14天神经元存活的缺陷。IBU可阻断LPS诱导的发热，但不能阻断LPS诱导的怀孕母鼠血浆细胞因子和皮质酮的增加。这表明产前LPS引起的神经发生缺陷不是由LPS诱导的发热或类花生酸诱导介导的，而是可能由LPS诱导的母体细胞因子或皮质酮增加介导的。
