Article

Preliminary evidence for a modulation of fetal dopaminergic development by maternal immune activation during pregnancy

Laboratory of Behavioural Neurobiology, ETH Zurich, Schorenstrasse 16, Schwerzenbach, Switzerland.
Neuroscience (Impact Factor: 3.36). 07/2008; 154(2):701-9. DOI: 10.1016/j.neuroscience.2008.04.031
Source: PubMed

ABSTRACT

Maternal infection during pregnancy is an environmental risk factor for the offspring to develop severe brain disorders, including schizophrenia and autism. However, only little is known about the neurodevelopmental mechanisms underlying the association between prenatal exposure to infection and the emergence of brain and behavioral dysfunctions in later life. Using a mouse model of prenatal immune challenge by the viral mimic polyriboinosinic-polyribocytidilic acid (PolyI:C), we explored the acute effects of maternal immune activation during pregnancy on the development of the fetal dopaminergic system, a neurotransmitter system known to be affected in schizophrenia and related disorders. We found that maternal immunological stimulation in early/middle pregnancy increased the number of mesencephalic dopamine neurons in the fetal brain at middle/late and late gestation. This effect was paralleled by changes in fetal expression of several genes known to be involved in dopamine neuron development, including the inductive signals sonic hedgehog (Shh) and fibroblast growth factor 8 (Fgf8), as well as transcription factors Nurr1 and Pitx3. These findings provide initial in vivo evidence for a modulation of fetal dopaminergic development by maternal immune activation during pregnancy. Additional investigations of the neurodevelopmental effects of prenatal immune challenge are thus clearly warranted in order to further validate whether abnormal dopaminergic development may be a critical neuropathological mechanism underlying the precipitation of schizophrenia-like brain and behavioral dysfunctions emerging after in utero exposure to infection.

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    • "Additionally, immune and inflammatory processes in prenatal and perinatal stages are suggested to play crucial roles in the vulnerability to schizophrenia. Munc18-OE mice show symptoms similar to those induced in adult offspring by the polyinosinic:polycytidylic acid (poly I:C) maternal immune activation model of schizophrenia [48-50]. It would be interesting to evaluate neuroinflammation in other animal models to elucidate whether this potential correlation between a disruption in the levels of proinflammatory markers and schizophrenia is present. "
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    ABSTRACT: Background An accumulating body of evidence points to the significance of neuroinflammation and immunogenetics in schizophrenia, and an imbalance of cytokines in the central nervous system (CNS) has been suggested to be associated with the disorder. Munc18-overexpressing mice (Munc18-OE) have provided a model for the study of the alterations that may underlie the symptoms of subjects with schizophrenia. The aim of the present study was to elucidate the involvement of neuroinflammation and cytokine imbalance in this model. Methods Cytokines were evaluated in the cortex and the striatum of Munc18-OE and wild-type (WT) mice by enzyme-linked immunosorbent assay (ELISA). Protein levels of specific microglia and macrophage, astrocytic and neuroinflammation markers were quantified by western blot in the cortex and the striatum of Munc18-OE and WT mice. Results Each cytokine evaluated (Interferon-gamma (IFN-γ), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-2 (IL-2) and CCL2 chemokine) was present at higher levels in the striatum of Munc18-OE mice than WT. Cortical TNF-α and IL-2 levels were significantly lower in Munc18-OE mice than WT mice. The microglia and macrophage marker CD11b was lower in the cortexes of Munc18-OE mice than WT, but no differences were observed in the striatum. Glial Fibrillary Acidic Protein (GFAP) and Nuclear Factor-kappaB (NF-κB)p65 levels were not different between the groups. Interleukin-1beta (IL-1β) and IL-6 levels were beneath detection limits. Conclusions The disrupted levels of cytokines detected in the brain of Munc18-OE mice was found to be similar to clinical reports and endorses study of this type for analysis of this aspect of the disorder. The lower CD11b expression in the cortex but not in the striatum of the Munc18-OE mice may reflect differences in physiological activity. The cytokine expression pattern observed in Munc18-OE mice is similar to a previously published model of schizophrenia caused by maternal immune activation. Together, these data suggest a possible role for an immune imbalance in this disorder.
    Full-text · Article · Jul 2014 · Journal of Neuroinflammation
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    • "For example, MIA has been associated with impaired object recognition (Coyle et al., 2009; Graciarena et al., 2010) and spatial memory (Golan et al., 2005; Howland et al., 2012), decreased prepulse (Fortier et al., 2007; Wolff and Bilkey, 2010) and latent (Bitanihirwe et al., 2010; Meyer et al., 2006) inhibition, increased amphetamine induced locomotion (Fortier et al., 2004; Poinkewitz et al., 2011), and altered social behaviors (Bitanihirwe et al., 2010; Hava et al., 2006; Malkova et al., 2012). Additionally, in animal models of MIA, the associated brain changes are reported to parallel the pathogenesis of schizophrenia and autism including diminished NMDA receptor functioning , imbalances in dopamine regulation, reductions in the glycoprotein reelin, and general immune dysregulation (Coyle et al., 2003; Meyer et al., 2008; see Patterson, 2009; Shi et al., 2003). Moreover, the behavioral impairments observed in offspring following MIA may be reversed by schizophrenia drug treatments (Shi et al., 2003). "
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    ABSTRACT: Modest environmental enrichment (EE) is well recognized to protect and rescue the brain from the consequences of a variety of insults. Although animal models of maternal immune activation (MIA) are associated with several neurodevelopmental impairments in both the behavioral and cognitive functioning of offspring, the impact of EE in protecting or reversing these effects has not been fully evaluated. In the present study, female Sprague-Dawley rats were randomized into EE (pair-housed in a large multi-level cage with toys, tubes and ramps) or animal care control (ACC; pair-housed in standard cages) conditions. Each pair was bred, following assignment to their housing condition, and administered 100 ug/kg of lipopolysaccharide (LPS) on gestational day 11. After birth, and until the end of the study, offspring were maintained in their respective housing conditions. EE protected against both the social and hypothalamic pituitary adrenal axis consequences of MIA in juvenile male rats, but surprisingly not against the spatial discrimination deficits or accompanying decrease in glutamate levels within the hippocampus (as measured via LCMS-MS). Based on these preliminary results, the mechanisms that underlie the sex-specific consequences that follow MIA appear to be dependent on environmental context. Together, this work highlights the importance of environmental complexity in the prevention of neurodevelopmental deficits following MIA.
    Full-text · Article · Jul 2014 · Brain Behavior and Immunity
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    • "For example, MIA has been associated with impaired object recognition (Coyle et al., 2009; Graciarena et al., 2010) and spatial memory (Golan et al., 2005; Howland et al., 2012), decreased prepulse (Fortier et al., 2007; Wolff and Bilkey, 2010) and latent (Bitanihirwe et al., 2010; Meyer et al., 2006) inhibition, increased amphetamine induced locomotion (Fortier et al., 2004; Poinkewitz et al., 2011), and altered social behaviors (Bitanihirwe et al., 2010; Hava et al., 2006; Malkova et al., 2012). Additionally, in animal models of MIA, the associated brain changes are reported to parallel the pathogenesis of schizophrenia and autism including diminished NMDA receptor functioning , imbalances in dopamine regulation, reductions in the glycoprotein reelin, and general immune dysregulation (Coyle et al., 2003; Meyer et al., 2008; see Patterson, 2009; Shi et al., 2003). Moreover, the behavioral impairments observed in offspring following MIA may be reversed by schizophrenia drug treatments (Shi et al., 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Modest environmental enrichment (EE) is well recognized to protect and rescue the brain from the consequences of a variety of insults. Although animal models of maternal immune activation (MIA) are associated with several neurodevelopmental impairments in both the behavioral and cognitive functioning of offspring, the impact of EE in protecting or reversing these effects has not been fully evaluated. In the present study, female Sprague-Dawley rats were randomized into EE (pair-housed in a large multi-level cage with toys, tubes and ramps) or animal care control (ACC; pair-housed in standard cages) conditions. Each pair was bred, following assignment to their housing condition, and administered 100 ug/kg of lipopolysaccharide (LPS) on gestational day 11. After birth, and until the end of the study, offspring were maintained in their respective housing conditions. EE protected against both the social and hypothalamic pituitary adrenal axis consequences of MIA in juvenile male rats, but surprisingly not against the spatial discrimination deficits or accompanying decrease in glutamate levels within the hippocampus (as measured via LCMS-MS). Based on these preliminary results, the mechanisms that underlie the sex-specific consequences that follow MIA appear to be dependent on environmental context. Together, this work highlights the importance of environmental complexity in the prevention of neurodevelopmental deficits following MIA.
    Full-text · Article · Jan 2014 · Brain Behavior and Immunity
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