Abstract
Autism is characterized by social deficits, repetitive behaviors, and cognitive inflexibility. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces autistic-like behaviors. To understand the causes of autistic-like behaviors, we evaluated maternal serum metal concentrations, which are involved in intrauterine development and infection/inflammation. We identified reduced maternal levels of zinc, magnesium, selenium and manganese after LPS exposure. Because LPS induced maternal hypozincemia, we treated dams with zinc in an attempt to prevent or ease the impairments in the offspring. We evaluated the social and cognitive autistic-like behaviors and brain tissues of the offspring to identify the central mechanism that triggers the development of autism. Prenatal LPS exposure impaired play behaviors and T-maze spontaneous alternations, i.e., it induced autistic-like behaviors. Prenatal LPS also decreased tyrosine hydroxylase levels and increased the levels of mammalian target of rapamycin (mTOR) in the striatum. Thus, striatal dopaminergic impairments may be related to autism. Moreover, excessive signaling through the mTOR pathway has been considered a biomarker of autism, corroborating our rat model of autism. Prenatal zinc treatment prevented these autistic-like behaviors and striatal dopaminergic and mTOR disturbances in the offspring induced by LPS exposure. The present findings revealed a possible relation between maternal hypozincemia during gestation and the onset of autism. Furthermore, prenatal zinc administration appears to have a beneficial effect on the prevention of autism.
Highlights
Prenatal viral and bacterial infections impair short- and long-term behavior and central nervous system activity in animals [1,2,3]
Because it was observed that maternal LPS exposure induced hypozincemia, the dams were treated with zinc in an attempt to prevent or ameliorate the impairments in the offspring
Infections associated with immunological events during the early/middle fetal stages (e.g., gestational day (GD) 8–10 in rats and mice) may have a stronger impact on neurodevelopment compared with infections that occur during late-stage pregnancy
Summary
Prenatal viral and bacterial infections impair short- and long-term behavior and central nervous system activity in animals [1,2,3]. Maternal immune activation can induce neuropsychiatric disorders, including schizophrenia and autism [4,5,6,7]. Previous investigations by our group have shown that prenatal treatment of rats on gestational day (GD) 9.5 with lipopolysaccharide (LPS; 100 μg/kg, intraperitoneal [i.p.]), an endotoxin that mimics infection with gram-negative bacteria, impaired communication and socialization and induced repetitive/restricted behavior in male offspring. The behavior of female offspring was not altered [14, 15] These results suggest that our model of prenatal LPS exposure induces autism-like behavior in offspring [15]. The effects of maternal LPS exposure on the developing fetal brain have been suggested to be mediated by the induction of proinflammatory cytokines within the maternal circulation and placenta [20,21,22]
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