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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    • "Such abnormalities have indeed been noted by numerous previous investigations using prenatal poly(I:C) models in rodents (Dickerson et al., 2010, 2014; Savanthrapadian et al., 2013; Wolff and Bilkey, 2015; Zhang and van Praag, 2015). Furthermore, the synaptic deficits may also contribute to the cognitive impairments that have frequently been observed following prenatal immune activation (reviewed in Boksa (2010), Harvey and Boksa (2012), Meyer and Feldon (2010), Reisinger et al. (2015)). "
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    ABSTRACT: Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre- and postsynaptic deficits. Using a well-established mouse model of maternal exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)-exposed and control mothers. We found that prenatal immune activation induced adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early-life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial anomalies or systemic inflammation, adult offspring exposed to prenatal immune activation displayed increased hippocampal IL-1β levels. Taken together, our findings demonstrate that age-dependent synaptic deficits and abnormal pro-inflammatory cytokine expression can occur during postnatal brain maturation in the absence of microglial anomalies or systemic inflammation.
    Full-text · Article · Sep 2015 · Brain Behavior and Immunity
    • "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.
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    • "The role of immune activation in the generation of acute seizures and epilepsy has been investigated in animal models. While the role of inflammation during or after seizures in several models has been more systematically studied (Vezzani et al. 2011b, 2012), in comparison, only few studies have been pointed to the study of the immune system response and seizures following infections or the injection of LPS (Harvey and Boksa 2012). Some interesting results have been obtained studying seizures' generation in models of bacterial meningitis involving injection of group B streptococcus in infant rats (Kim et al. 1995; Kolarova et al. 2003) and models of viral CNS infection involving administration of Theiler's murine encephalomyelitis virus in young mice (Libbey and Fujinami 2011; Libbey et al. 2011). "
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    ABSTRACT: It is widely acknowledged that immune system influences several aspects of the central nervous system. Literature data have shown that immune system and autoimmune response play an important role in the pathogenesis of several neurodegenerative/neurological diseases (i.e Parkinson’s and Alzheimer’s Diseases, Multiple Sclerosis). However, very recent evidences of specific antibodies found in epileptic encephalitis, the good response to immune therapy in refractory epileptic syndromes and the strong relationship between systemic autoimmune disease and epilepsy suggest a plausible role for the immune system also in paroxysmal neurological disorders. In fact, an immune hypothesis represents a new way to approach epilepsy and could contribute to clarify several unanswered questions in the next future. In this review, we analysed these points mimicking a tour around current evidences from experimental animal models to clinical suggestions.
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