Prenatal and postnatal animal models of immune activation: Relevance to a range of neurodevelopmental disorders

Department of Psychiatry, McGill University, Douglas Mental Health University Institute, Verdun, Quebec, Canada H4H 1R3.
Developmental Neurobiology (Impact Factor: 3.37). 10/2012; 72(10):1335-48. DOI: 10.1002/dneu.22043
Source: PubMed


Epidemiological evidence has established links between immune activation during the prenatal or early postnatal period and increased risk of developing a range of neurodevelopment disorders in later life. Animal models have been used to great effect to explore the ramifications of immune activation during gestation and neonatal life. A range of behavioral, neurochemical, molecular, and structural outcome measures associated with schizophrenia, autism, cerebral palsy, and epilepsy have been assessed in models of prenatal and postnatal immune activation. However, the epidemiology-driven disease-first approach taken by some studies can be limiting and, despite the wealth of data, there is a lack of consensus in the literature as to the specific dose, timing, and nature of the immunogen that results in replicable and reproducible changes related to a single disease phenotype. In this review, we highlight a number of similarities and differences in models of prenatal and postnatal immune activation currently being used to investigate the origins of schizophrenia, autism, cerebral palsy, epilepsy, and Parkinson's disease. However, we describe a lack of synthesis not only between but also within disease-specific models. Our inability to compare the equivalency dose of immunogen used is identified as a significant yet easily remedied problem. We ask whether early life exposure to infection should be described as a disease-specific or general vulnerability factor for neurodevelopmental disorders and discuss the implications that either classification has on the design, strengths and limitations offuture experiments. © 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.

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    • "What is more important is to note that the immune components not only enhance the risk and progression of schizophrenia by mounting immuno-inflammatory responses but also by influencing neurodevelopmental, neurometabolic, neuroendocrine and other etilogical pathways (Debnath et al. 2015; Guest et al. 2011; Vuillermot et al. 2010). For example, maternal immune activation and/or developmental neuroinflammation due to prenatal adversities was shown to impair crucial phases of neurodevelopment and increase the risk of schizophrenia in the offspring (Harvey and Boksa 2012; Meyer 2013). The components and mediators of the immune system also interact potentially with the neurotransmitters and modulate dopaminergic as well as glutamatergic neurotransmission in schizophrenia (Song et al. 1999; Muller and Schwarz 2006; Zalcman et al. 1994). "
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    ABSTRACT: Schizophrenia is a severe and highly complex neurodevelopmental disorder with an unknown etiopathology. Recently, immunopathogenesis has emerged as one of the most compelling etiological models of schizophrenia. Over the past few years considerable research has been devoted to the role of innate immune responses in schizophrenia. The findings of such studies have helped to conceptualize schizophrenia as a chronic low-grade inflammatory disorder. Although the contribution of adaptive immune responses has also been emphasized, however, the precise role of T cells in the underlying neurobiological pathways of schizophrenia is yet to be ascertained comprehensively. T cells have the ability to infiltrate brain and mediate neuro-immune cross-talk. Conversely, the central nervous system and the neurotransmitters are capable of regulating the immune system. Neurotransmitter like dopamine, implicated widely in schizophrenia risk and progression can modulate the proliferation, trafficking and functions of T cells. Within brain, T cells activate microglia, induce production of pro-inflammatory cytokines as well as reactive oxygen species and subsequently lead to neuroinflammation. Importantly, such processes contribute to neuronal injury/death and are gradually being implicated as mediators of neuroprogressive changes in schizophrenia. Antipsychotic drugs, commonly used to treat schizophrenia are also known to affect adaptive immune system; interfere with the differentiation and functions of T cells. This understanding suggests a pivotal role of T cells in the etiology, course and treatment of schizophrenia and forms the basis of this review.
    Journal of Neuroimmune Pharmacology 07/2015; DOI:10.1007/s11481-015-9626-9 · 4.11 Impact Factor
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    • "Rodent-based MIA models of neurodevelopmental disorders were developed to mimic aspects of these phenomena in a laboratory setting. It is important to note however that in addition to ASD, the MIA paradigm has also been used to model schizophrenia, which has similarly been associated with prenatal immune disturbances in the patient population [20], [21], [22]. Maternal immune activation is typically induced by injecting lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (Poly IC) into pregnant female rats or mice during gestation to mimic a bacterial or viral infection, respectively [23]. "
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    ABSTRACT: Autism spectrum disorders are neurodevelopmental disorders characterized by two core symptoms; impaired social interactions and communication, and ritualistic or repetitive behaviors. Both epidemiological and biochemical evidence suggests that a subpopulation of autistics may be linked to immune perturbations that occurred during fetal development. These findings have given rise to an animal model, called the "maternal immune activation" model, whereby the offspring from female rodents who were subjected to an immune stimulus during early or mid-pregnancy are studied. Here, C57BL/6 mouse dams were treated mid-gestation with saline, lipopolysaccharide (LPS) to mimic a bacterial infection, or polyinosinic:polycytidylic acid (Poly IC) to mimic a viral infection. Autism-associated behaviors were examined in the adult offspring of the treated dams. Behavioral tests were conducted to assess motor activity, exploration in a novel environment, sociability, and repetitive behaviors, and data analyses were carried independently on male and female mice. We observed a main treatment effect whereby male offspring from Poly IC-treated dams showed reduced motor activity. In the marble burying test of repetitive behavior, male offspring but not female offspring from both LPS and Poly IC-treated mothers showed increased marble burying. Our findings indicate that offspring from mothers subjected to immune stimulation during gestation show a gender-specific increase in stereotyped repetitive behavior.
    PLoS ONE 08/2014; 9(8):e104433. DOI:10.1371/journal.pone.0104433 · 3.23 Impact Factor
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    • "Placenta system is susceptible to the effects of maternal immune activation [8] [16]. In agreement with this, we have recently shown, using the well-characterised superior cervical ganglion (SCG) in vitro model [17], that the growth of fetal neurons can be inhibited by the proinflammatory cytokine, interleukin (IL)-1b, at late embryonic and early postnatal stages of development, but not before or after this developmental window of sensitivity [18]. "
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    ABSTRACT: Introduction: During pregnancy, maternal infection at different stages of gestation increases the risk of developing several psychiatric and neurological disorders later in life for affected offspring. As placental health is intrinsically linked to neurodevelopmental outcome, maternal infection may adversely affect the placenta at or before the gestational stages it affects fetal neurodevelopment. Here we examined this premise. Methods: Pregnant-Sprague Dawley rats were administered saline or lipopolysaccharide by intraperitoneal injection on embryonic days 12-18. We then examined a number of key placental inflammatory and endocrine mediators, along with fetal, birth and neuronal characteristics at different stages of development. Results: Maternal exposure to lipopolysaccharide at later gestational ages significantly increased pro-inflammatory IL-1β expression and reduced placental HSD11B2 expression. This was accompanied by a reduction in placental weight and embryo number without an effect on embryo weight or crown-rump length. In utero lipopolysaccharide exposure at later gestational ages also impaired the growth of neurons from affected offspring. Discussion: These data show that maternal infection at later gestational ages modifies placental inflammatory and endocrine mediators that may adversely affect the growth of developing neurons in affected offspring.
    Placenta 06/2014; 35(8). DOI:10.1016/j.placenta.2014.06.001 · 2.71 Impact Factor
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