Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response

Section on Functional Neuroanatomy, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA.
Brain Behavior and Immunity (Impact Factor: 5.89). 01/2012; 26(4):623-34. DOI: 10.1016/j.bbi.2012.01.015
Source: PubMed


Maternal immune activation (MIA) is a risk factor for the development of schizophrenia and autism. Infections during pregnancy activate the mother's immune system and alter the fetal environment, with consequential effects on CNS function and behavior in the offspring, but the cellular and molecular links between infection-induced altered fetal development and risk for neuropsychiatric disorders are unknown. We investigated the immunological, molecular, and behavioral effects of MIA in the offspring of pregnant Sprague-Dawley rats given an intraperitoneal (0.25 mg/kg) injection of lipopolysaccharide (LPS) on gestational day 15. LPS significantly elevated pro-inflammatory cytokine levels in maternal serum, amniotic fluid, and fetal brain at 4 h, and levels decreased but remained elevated at 24 h. Offspring born to LPS-treated dams exhibited reduced social preference and exploration behaviors as juveniles and young adults. Whole genome microarray analysis of the fetal brain at 4 h post maternal LPS was performed to elucidate the possible molecular mechanisms by which MIA affects the fetal brain. We observed dysregulation of 3285 genes in restricted functional categories, with increased mRNA expression of cellular stress and cell death genes and reduced expression of developmentally-regulated and brain-specific genes, specifically those that regulate neuronal migration of GABAergic interneurons, including the Distal-less (Dlx) family of transcription factors required for tangential migration from progenitor pools within the ganglionic eminences into the cerebral cortex. Our results provide a novel mechanism by which MIA induces the widespread down-regulation of critical neurodevelopmental genes, including those previously associated with autism.

    • "Thus, although protocols of maternal immune activation urge for outcome replicability and reproducibility, a spectrum of behavioral abnormalities is possible [7]. This is not at all unexpected, having in mind that LPS administrated on embryonic day 15 (E15) dysregulated as many as 3285 genes in rat fetal brain and induced widespread down-regulation of critical neurodevelopmental genes [11]. In a recent review of limitations in schizophrenia and autism models, it was proposed that acute prenatal neuroinflammation may predispose and contribute to pathological features shared by both disorders, whereas schizophrenia-and autism-specific phenotypes may be governed by subsequent latent and persistent inflammation, respectively [12]. "
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    ABSTRACT: Numerous basic and epidemiological studies have connected prenatal maternal immune activation with the occurrence of schizophrenia and/or autism. Depending on subtle differences in protocols of the used animal model, a variety of behavioral abnormalities has been reported. This study investigated behavioral differences in Wistar rat offspring of both genders, exposed to the 100μg/kg per day dose of lipopolysaccharide (LPS) in late embryogenesis (embryonic days 15 and 16), while tested at their adolescent and young adult age (postnatal days 40 and 60, respectively). Immune activation was confirmed by detecting high levels of TNF-α and IL-6 in dam blood withdrawn 2h after the first dose of LPS. The animals were assessed in three consecutive trials of locomotor activity (novelty exploration, response to i.p. saline injection and challenge with 0.5mg/kg amphetamine), Morris water maze and social interaction tests. Overt behavioral dysfunction was perceived in adult rats only, and these changes were gender-distinctive. When compared with control rats, LPS females displayed baseline hypolocomotion and a decreased reactivity to amphetamine, while LPS males exhibited spatial learning (acquisition trials) and memory (probe trial) impairments. Prenatal treatment did not affect the time spent in social interaction. As maternal exposure to LPS in late gestation resulted in behavioral changes in offspring in early adulthood, it may model schizophrenia-like, but not autism-like endophenotypes. However, lack of a potentiated response to amphetamine testified that this model could not mimic positive symptoms, but rather certain traits of cognitive dysfunction and deficit symptoms, in males and females, respectively.
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    • "In our results, a decrease on the level of IFN-g was verified, which would explain the reduction in the number of hippocampal cells in the offspring of dams envenomed during pregnancy observed in previous experiments (Dorce et al., 2010). The results obtained with LPS in our work agree with the data in the literature (Erickson and Banks, 2011; Golan et al., 2005; Oskvig et al., 2012). The cytokine response to the venom was subtle, sometimes consistent with the LPS reference and other times, not. "
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    ABSTRACT: Due to the high incidence of scorpion stings in Brazil, pregnant women are among the possible victims. Cytokines are important during the pregnancy, and scorpion venoms can change their release. We evaluated the levels of some cytokines in the fetuses after the treatment of pregnant rats with the T. bahiensis scorpion venom. The concentration of some of them is altered and can be responsible for the effects previously observed on innate reflexes, and the physical and behavioral development of the offspring. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Jun 2015 · Toxicon
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    • "Increased anxiety in the elevated plus maze have been shown in male and female adolescent and adult offspring [24], [25], [26]. Assessment of open-field activity has yielded mixed results, with decreased nose-hole pokes [27] and decreased activity and centre entries [28], no change in locomotor activity [27], [29], or increased activity [30] being observed. While there is increasing attention on investigating possible sex differences following MIA (e.g., [30]), most published studies, to date, are with male rodents. "
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    ABSTRACT: Alterations in the composition of the gut microbiome and/or immune system function may have a role in the development of autism spectrum disorders (ASD). The current study examined the effects of prenatal and early life administration of lipopolysaccharide (LPS), a bacterial mimetic, and the short chain fatty acid, propionic acid (PPA), a metabolic fermentation product of enteric bacteria, on developmental milestones, locomotor activity, and anxiety-like behavior in adolescent male and female offspring. Pregnant Long-Evans rats were subcutaneously injected once a day with PPA (500 mg/kg) on gestation days G12-16, LPS (50 µg/kg) on G15-16, or vehicle control on G12-16 or G15-16. Male and female offspring were injected with PPA (500 mg/kg) or vehicle twice a day, every second day from postnatal days (P) 10-18. Physical milestones and reflexes were monitored in early life with prenatal PPA and LPS inducing delays in eye opening. Locomotor activity and anxiety were assessed in adolescence (P40-42) in the elevated plus maze (EPM) and open-field. Prenatal and postnatal treatments altered behavior in a sex-specific manner. Prenatal PPA decreased time spent in the centre of the open-field in males and females while prenatal and postnatal PPA increased anxiety behavior on the EPM in female rats. Prenatal LPS did not significantly influence those behaviors. Evidence for the double hit hypothesis was seen as females receiving a double hit of PPA (prenatal and postnatal) displayed increased repetitive behavior in the open-field. These results provide evidence for the hypothesis that by-products of enteric bacteria metabolism such as PPA may contribute to ASD, altering development and behavior in adolescent rats similar to that observed in ASD and other neurodevelopmental disorders.
    Full-text · Article · Jan 2014 · PLoS ONE
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