Early effects of lipopolysaccharide-induced inflammation on foetal brain development in rat

Intellectual and Developmental Disability Research Center, Jane and Terry Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at the University of California at Los Angeles, 90095, USA.
ASN Neuro (Impact Factor: 4.02). 10/2011; 3(4). DOI: 10.1042/AN20110027
Source: PubMed


Studies in humans and animal models link maternal infection and imbalanced levels of inflammatory mediators in the foetal brain to the aetiology of neuropsychiatric disorders. In a number of animal models, it was shown that exposure to viral or bacterial agents during a period that corresponds to the second trimester in human gestation triggers brain and behavioural abnormalities in the offspring. However, little is known about the early cellular and molecular events elicited by inflammation in the foetal brain shortly after maternal infection has occurred. In this study, maternal infection was mimicked by two consecutive intraperitoneal injections of 200 μg of LPS (lipopolysaccharide)/kg to timed-pregnant rats at GD15 (gestational day 15) and GD16. Increased thickness of the CP (cortical plate) and hippocampus together with abnormal distribution of immature neuronal markers and decreased expression of markers for neural progenitors were observed in the LPS-exposed foetal forebrains at GD18. Such effects were accompanied by decreased levels of reelin and the radial glial marker GLAST (glial glutamate transporter), and elevated levels of pro-inflammatory cytokines in maternal serum and foetal forebrains. Foetal inflammation elicited by maternal injections of LPS has discrete detrimental effects on brain development. The early biochemical and morphological changes described in this work begin to explain the sequelae of early events that underlie the neurobehavioural deficits reported in humans and animals exposed to prenatal insults.

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Available from: Cristina A Ghiani,
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    • "Due in part to this immune response, gram-negative bacterial infections, such as bacterial vaginosis (BV), have been shown to cause complications in early pregnancy that may lead to fetal death in humans. In addition, gram-negative bacterial endotoxins, such as LPS, have been found to be considerably damaging to preimplantation and implantation stage embryos (Ling et al., 2002b; Deb et al., 2004; Aroutcheva et al., 2008), and the developing brain (Ling et al., 2002a, 2002b; Ghiani et al., 2011; Xu et al., 2013). In the brain, LPS causes an inflammatory response through the activation of microglia and subsequent release of proinflammatory cytokines (Laurenzi et al., 2001; Park et al., 2007; Dutta et al., 2008; Poulose et al., 2012). "
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    ABSTRACT: The purpose of this study was to determine the effect of dietary supplementation with the anti-inflammatory compound resveratrol in pregnant dams on lipopolysaccharide (LPS)-induced dopaminergic deficits in pups exposed to LPS in utero. Gravid female rats were fed a resveratrol-enriched diet during gestational days 3–22.5 (E3 - E22.5) and received an intraperitoneal (i.p.) injection of 1 mg/kg LPS at E10.5. The striata were isolated from the pups at postnatal day 10 (P10) and P21. LPS-induced dopaminergic deficits were noted at P21, but not P10. These DA deficits at P21 were exhibited by a loss of DA and DA metabolite [3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] levels and tyrosine hydroxylase (TH) expression in the striatum. The LPS-induced loss of DA, DA metabolites, and TH expression were attenuated in the striata of pups from the dams fed the resveratrol-supplemented diet. These data suggest that a resveratrol-supplemented diet may restore homeostasis of the striatal DA neuronal system following disruption by LPS.
    Brain Research 05/2014; DOI:10.1016/j.brainres.2014.05.028 · 2.84 Impact Factor
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    • "size in the CA1 (P14) Makinodan et al. (2008) Decreased myelin thickness in the CA1 (P14) Makinodan et al. (2008) E15 LPS 5000 IU/kg Rat Increased number of proliferating cells in the GCL (P3-P14) Jiang et al. (2012) E15/16 LPS 100 ␮g/kg Rat Decreased number of GAD67+ cells in the DG (P14 and 28) Nouel et al. (2012) Decreased number of reelin+ cells in the DG (P14) Nouel et al. (2012) Decreased cell proliferation in the DG (P14) Cui et al. (2009) Decrease in cell survival of cells born postnatally (P14) Cui et al. (2009) 200 ␮g/kg Rat Increased hippocampal thickness (E18) Ghiani et al. (2011) E17 Poly(I:C) 5 mg/kg Mouse Decreased number of newly-born neurons in the outer granular layer (P24) Meyer et al. (2006) Increased apoptosis in the DG (P24) Meyer et al. (2006) LPS 120 ␮g/kg Mouse Shorter DG (P14) Golan et al. (2005) Thicker CA1 (P7) but thinner CA1 at P14 Golan et al. (2005) E18/19 LPS 50 ␮g/kg Rat Decreased DG cell survival born during development (P14) Cui et al. (2009) Decrease in cell survival of cells born postnatally (P14) Cui et al. (2009) "
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    ABSTRACT: While the detrimental impact of inflammation on adult hippocampal neurogenesis and associated behaviors has recently gained credence, the effects of inflammation on the developing brain is an area of research which is quickly gaining momentum, and a growing number of research articles on this topic have been published in recent years. Indeed, we now know that pro-inflammatory mediators negatively influence both hippocampal neurogenesis and neuronal cytoarchitecture during brain development. Here we present a comprehensive review of the current literature on inflammation-induced changes in hippocampal neurogenesis during early life and the consequent behavioral deficits which may ensue in later life. We also offer insights into the cellular and molecular mechanisms underlying the hippocampal-dependant behavioral changes observed in neurodevelopmental disorders, particularly in those where cognitive dysfunction plays a major role. We further consider whether early-life inflammation-induced changes in hippocampal neurogenesis may contribute to the onset of mood and cognitive deficits in later life.
    Neuroscience & Biobehavioral Reviews 01/2014; 40. DOI:10.1016/j.neubiorev.2014.01.004 · 8.80 Impact Factor
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    • "Increased cytokine gene expression by fetal brain has not been shown in the maternal LPS model except in some studies that used a much higher dose of LPS than what was used in our study (Cai et al., 2000; Lasala and Zhou, 2007). Little is known about the acute biological effects of maternal LPS on the fetal brain aside from one report of maternal LPSinduced gene changes in the fetal brain (Liverman et al., 2006) and a recent report showing some structural changes and perturbed neural development in rat cerebral cortex at gestational day 18 following LPS administered maternally at gestational days 15 and 16 (Ghiani et al., 2011). Thus, although it has been demonstrated that MIA alters behavioral and biological outcomes in juvenile and adult offspring, the mechanisms by which this immune reaction ultimately disrupt brain and behavioral development remain unclear (Boksa, 2010). "
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    ABSTRACT: 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.
    Brain Behavior and Immunity 01/2012; 26(4):623-34. DOI:10.1016/j.bbi.2012.01.015 · 5.89 Impact Factor
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