Nawa H, Takei N. Recent progress in animal modeling of immune inflammatory processes in schizophrenia: implication of specific cytokines. Neurosci Res 56: 2-13

Division of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Niigata, Japan.
Neuroscience Research (Impact Factor: 1.94). 10/2006; 56(1):2-13. DOI: 10.1016/j.neures.2006.06.002
Source: PubMed


Epidemiologic studies demonstrate significant environmental impact of maternal viral infection and obstetric complications on the risk of schizophrenia and indicate their detrimental influences on brain development in this disorder. Based on these findings, animal models for schizophrenia have been established using double stranded RNA, bacterial lipopolysaccharides, hippocampal lesion, or prenatal/perinatal ischemia. Key molecules regulating such immune/inflammatory reactions are cytokines, which are also involved in brain development, regulating dopaminergic and GABAergic differentiation, and synaptic maturation. Specific members of the cytokine family, such as interleukin-1, epidermal growth factor, and neuregulin-1, are induced after infection and brain injury; therefore, certain cytokines are postulated to have a central role in the neurodevelopmental defects of schizophrenia. Recently, to test this hypothesis, a variety of cytokines were administered to rodent pups. Cytokines administered in the periphery penetrated the immature blood-brain barrier and perturbed phenotypic neural development. Among the many cytokines examined, epidermal growth factor (or potentially other ErbB1 ligands) and interleukin-1 specifically induced the most severe and persistent behavioral and cognitive abnormalities, most of which were ameliorated by antipsychotics. These animal experiments illustrate that, during early development, these cytokine activities in the periphery perturbs normal brain development and impairs later psychobehavioral and/or cognitive traits. The neurodevelopmental and behavioral consequences of prenatal/perinatal cytokine activity are compared with those of other schizophrenia models and cytokine interactions with genes are also discussed in this review.

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    • "In infants, LPS is most studied in models of brain injury where it can induce subtle reductions in myelin or frank white matter damage [reviewed in (Wang, Rousset, Hagberg, & Mallard, 2006)]. In infants, but not adults, LPS readily crosses the blood-brain barrier and stimulates production of TNF-a, IL1a, IL-2, IL-6, and IL-10 (Nawa & Takei, 2006). However, there is tolerance to the immune and other (e.g., activation of the corticotrope axis) effects of LPS following repeated injection in adults and infants (e.g., Bumiller, Gotz, Rohde, & Dorner, 1999; Chautard, Spinedi, Voirol, Pralong, & Gaillard, 1999). "
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    ABSTRACT: Pain is a serious problem for infants and children and treatment options are limited. Moreover, infants born prematurely or hospitalized for illness likely have concurrent infection that activates the immune system. It is now recognized that the immune system in general and glia in particular influence neurotransmission and that the neural bases of pain are intimately connected to immune function. We know that injuries that induce pain activate immune function and suppressing the immune system alleviates pain. Despite this advance in our understanding, virtually nothing is known of the role that the immune system plays in pain processing in infants and children, even though pain is a serious clinical issue in pediatric medicine. This brief review summarizes the existing data on immune-neural interactions in infants, providing evidence for the immaturity of these interactions. © 2014 Wiley Periodicals, Inc. Dev Psychobiol.
    Developmental Psychobiology 12/2014; 56(8). DOI:10.1002/dev.21229 · 3.31 Impact Factor
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    • "In line with its expression on synaptic membranes, MHC I is thought to be essential for synapse formation and plasticity [31]. Cytokines, molecules that are linked to communication between immune cells, play an important role in neurodevelopment [32], especially the pro-inflammatory cytokines [33]. IL-1 is involved in maintenance of long term potentiation [34], as well as region specific induction and inhibition of neural progenitor cell proliferation [35]. "
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    ABSTRACT: Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by deficits in social interactions, communication, and increased stereotypical repetitive behaviors. The immune system plays an important role in neurodevelopment, regulating neuronal proliferation, synapse formation and plasticity, as well as removing apoptotic neurons. Immune dysfunction in ASD has been repeatedly described by many research groups across the globe. Symptoms of immune dysfunction in ASD include neuroinflammation, presence of autoantibodies, increased T cell responses, and enhanced innate NK cell and monocyte immune responses. Moreover these responses are frequently associated with more impairment in core ASD features including impaired social interactions, repetitive behaviors and communication. In mouse models replacing immune components in animals that exhibit autistic relevant features leads to improvement in behavior in these animals. Taken together this research suggests that the immune dysfunction often seen in ASD directly affects aspects of neurodevelopment and neurological processes leading to changes in behavior. Discussion of immune abnormalities in ASD will be the focus of this review. Copyright © 2014. Published by Elsevier B.V.
    Immunology Letters 11/2014; 163(1):49-55. DOI:10.1016/j.imlet.2014.11.006 · 2.51 Impact Factor
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    • "Besides reduced levels of GABAergic markers (Akbarian and Huang, 2006; Fatemi et al., 2001; Guidotti et al., 2000), white matter disturbances are a prominent finding in brains of schizophrenia patients (Bagary et al., 2003; Foong et al., 2000; Kubicki et al., 2005) and have been proposed to explain the course of the disease (Scheel et al., 2013). Administration of poly I:C or LPS triggers the activation of microglia with the subsequent release of pro-inflammatory cytokines (Dahlgren et al., 2006; Nawa and Takei, 2006) to which the cerebral white matter appears to be particularly vulnerable to (Chew et al., 2013). In fact, delayed myelination and altered axonal development has been reported after prenatal poly I:C administration in mice (Makinodan et al., 2008) but also following maternal LPS-infection in rat neonates (Rousset et al., 2008). "
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    ABSTRACT: Maternal infection during pregnancy increases the risk for the offspring to develop schizophrenia. Gender differ-ences can be seen in various features of the illness and sex steroid hormones (e.g. estrogen) have strongly been implicated in the disease pathology. In the present study, we evaluated sex differences in the effects of prenatal exposure to a bacterial endotoxin (lipopolysaccharide, LPS) in rats. Pregnant dams received LPS-injections (100 μg/kg) at gestational day 15 and 16. The offspring was then tested for prepulse inhibition (PPI), locomotor activity, anxiety-like behavior and object recognition memory at various developmental time points. At postnatal day (PD) 33 and 60, prenatally LPS-exposed rats showed locomotor hyperactivity which was similar in male and female offspring. Moreover, prenatal LPS-treatment caused PPI deficits in pubertal (PD45) and adult (PD90) males while PPI impairments were found only at PD45 in prenatally LPS-treated females. Following prenatal LPS-administration, recognition memory for objects was impaired in both sexes with males being more severely affected. Additionally, we assessed prenatal infection-induced alterations of parvalbumin (Parv) expression and myelin fiber density. Male offspring born to LPS-challenged mothers showed decreased myelination in cortical and limbic brain regions as well as reduced numbers of Parv-expressing cells in the medial prefrontal cortex (mPFC), hippocampus and entorhinal cortex. In contrast, LPS-exposed female rats showed only a modest de-crease in myelination and Parv immunoreactivity. Collectively, our data indicate that some of the prenatal im-mune activation effects are sex dependent and further strengthen the importance of taking into account gender differences in animal models of schizophrenia.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 10/2014; 57:17. DOI:10.1016/j.pnpbp.2014.10.004 · 3.69 Impact Factor
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