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      Maternal immune activation: implications for neuropsychiatric disorders

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      Science (New York, N.Y.)

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          Abstract

          Epidemiological evidence implicates maternal infection as a risk factor for autism spectrum disorder and schizophrenia. Animal models corroborate this link and demonstrate that maternal immune activation (MIA) alone is sufficient to impart lifelong neuropathology and altered behaviors in offspring. This review describes common principles revealed by these models, highlighting recent findings that strengthen their relevance for schizophrenia and autism and are starting to reveal the molecular mechanisms underlying the effects of MIA on offspring. The role of MIA as a primer for a much wider range of psychiatric and neurologic disorders is also discussed. Finally, the need for more research in this nascent field and the implications for identifying, and developing new treatments for, individuals at heightened risk for neuro-immune disorders are considered.

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          Most cited references56

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          Abnormal neural oscillations and synchrony in schizophrenia.

          Converging evidence from electrophysiological, physiological and anatomical studies suggests that abnormalities in the synchronized oscillatory activity of neurons may have a central role in the pathophysiology of schizophrenia. Neural oscillations are a fundamental mechanism for the establishment of precise temporal relationships between neuronal responses that are in turn relevant for memory, perception and consciousness. In patients with schizophrenia, the synchronization of beta- and gamma-band activity is abnormal, suggesting a crucial role for dysfunctional oscillations in the generation of the cognitive deficits and other symptoms of the disorder. Dysfunctional oscillations may arise owing to anomalies in the brain's rhythm-generating networks of GABA (gamma-aminobutyric acid) interneurons and in cortico-cortical connections.
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            Recapitulating adult human immune traits in laboratory mice by normalizing environment

            Our current understanding of immunology was largely defined in laboratory mice because of experimental advantages including inbred homogeneity, tools for genetic manipulation, the ability to perform kinetic tissue analyses starting with the onset of disease, and tractable models. Comparably reductionist experiments are neither technically nor ethically possible in humans. Despite revealing many fundamental principals of immunology, there is growing concern that mice fail to capture relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside 1–8 . Laboratory mice live in abnormally hygienic “specific pathogen free” (SPF) barrier facilities. Here we show that the standard practice of laboratory mouse husbandry has profound effects on the immune system and that environmental changes result in better recapitulation of features of adult humans. Laboratory mice lack effector-differentiated and mucosally distributed memory T cells, which more closely resembles neonatal than adult humans. These cell populations were present in free-living barn populations of feral mice, pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting a role for environment. Consequences of altering mouse housing profoundly impacted the cellular composition of the innate and adaptive immune system and resulted in global changes in blood cell gene expression patterns that more closely aligned with immune signatures of adult humans rather than neonates, altered the mouse’s resistance to infection, and impacted T cell differentiation to a de novo viral infection. These data highlight the impact of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modeling immunological events in free-living organisms, including humans.
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              Immune involvement in schizophrenia and autism: etiology, pathology and animal models.

              There is increasing evidence of immune involvement in both schizophrenia and autism. Of particular interest are striking abnormalities in the expression of immune-related molecules such as cytokines in the brain and cerebral spinal fluid (CSF). It is proposed that this represents a permanent state of brain immune dysregulation, which begins during early development. One possibility is that maternal infection, a known risk factor for schizophrenia and autism, sets this immune activation in motion. Several animal models are being used to investigate this hypothesis. There is also recent evidence that, among schizophrenic subjects, those associated with maternal infection display a distinctive pathology, which suggests that diverse causes for this disorder may explain some of its heterogeneity. The human and animal results related to immune involvement suggest novel therapeutic avenues based on immune interventions.
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                Author and article information

                Journal
                0404511
                7473
                Science
                Science
                Science (New York, N.Y.)
                0036-8075
                1095-9203
                10 October 2017
                19 August 2016
                20 October 2017
                : 353
                : 6301
                : 772-777
                Author notes
                [* ]Corresponding Author: A. Kimberley McAllister, Ph.D., Center for Neuroscience, UC Davis, One Shields Avenue, Davis, CA 95618, Phone: (530) 752-8114, kmcallister@ 123456ucdavis.edu
                Article
                PMC5650490 PMC5650490 5650490 nihpa911626
                10.1126/science.aag3194
                5650490
                27540164
                6bc14515-68d5-440d-8c7d-916c743c8c30
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