Abstract
Recent studies in rodents suggest that maternal immune activation (MIA) by viral infection is associated with schizophrenia and autism in offspring. Although maternal IL-6 is though t to be a possible mediator relating MIA induced these neuropsychiatric disorders, the mechanism remains to be elucidated. Previously, we reported that the maternal leukemia inhibitory factor (LIF)–placental ACTH–fetal LIF signaling relay pathway (maternal–fetal LIF signal relay) promotes neurogenesis of fetal cerebrum in rats. Here we report that the maternal–fetal LIF signal relay in mice is suppressed by injection of polyriboinosinic-polyribocytidylic acid into dams, which induces MIA at 12.5 days post-coitum. Maternal IL-6 levels and gene expression of placental suppressor of cytokine signaling 3 (Socs3) increased according to the severity of MIA and gene expression of placental Socs3 correlated with maternal IL-6 levels. Furthermore, we show that MIA causes reduction of LIF level in the fetal cerebrospinal fluid, resulting in the decreased neurogenesis in the cerebrum. These findings suggest that maternal IL-6 interferes the maternal–fetal LIF signal relay by inducing SOCS3 in the placenta and leads to decreased neurogenesis.
Highlights
Epidemiological studies show that maternal viral infection during pregnancy increases the risk of schizophrenia and autism in the offspring [1,2,3,4]
We demonstrated the relation of placental suppressor of cytokine signaling 3 (SOCS3), which negatively regulate gp130 mediated signalling by inhibiting the phosphorylation of STAT3 [16] and maternal IL-6 in maternal immune activation (MIA)
Concentration of adrenocorticotropic hormone (ACTH) in fetal serum (FS) showed chronological increment (Fig 1C). These results demonstrate that the maternal–fetal leukemia inhibitory factor (LIF) signal relay exist in mice as well as in rats
Summary
Epidemiological studies show that maternal viral infection during pregnancy increases the risk of schizophrenia and autism in the offspring [1,2,3,4]. Maternal immune activation (MIA) in rodents due to viral infection, not direct infection of the fetuses, is the main cause of schizophrenia and autism developed in the offspring [5]. Injection of polyriboinosinic-polyribocytidylic acid [poly (I:C)], a synthetic analog of double-stranded RNA, causes MIA and is used in rodents to mimic maternal viral infection. The injection induces a so-called cytokine storm: an increase in pro-inflammatory cytokine levels such as interleukin-6 (IL-6), tumour necrosis factor-α and interleukin-1β [6, 7]. PLOS ONE | DOI:10.1371/journal.pone.0129011 June 4, 2015
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