Maternal immune activation, cytokines, and the pathogenesis of autism

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DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) is a complex disease that appears to be caused by a combination of genetic changes and an environmental insult during very early development. Increasing evidence suggests that several such environmental insults work through mechanisms that converge to chronically activate cytokines during fetal and early postnatal brain development. The development of a mouse model for maternal infection has added strong support for a link between maternal immune activation (MIA) and some of the pathology characteristic of ASD. The most compelling MIA mouse model-PolyI:C injection-produces abnormalities in gene expression, neuroanatomy, neurochemistry, and behavioral changes that are similar to those in autistic individuals. Current evidence indicates that these effects of MIA on fetal brain development are mediated by cytokines that cross the placenta. Although little is known about how maternal cytokines alter fetal brain development, the most likely possibility that we will test in this proposal is that MIA leads to chronic neuroinflammation that alters brain development and behavior and may contribute to the symptoms and pathology of ASD. Although cytokines are most often thought of as mediating an immune response, these small proteins and their receptors are found in the healthy, developing CNS where they play important roles in neural development and plasticity. Since cytokines mediate the immune response, are present in the developing cortex, and alter cortical plasticity and connectivity, factors that alter cytokines in the developing brain may lead to changes in synaptic connectivity that contribute to ASD. The goals of this proposal are to define the full complement of cytokines that are changed in specific regions of the CNS of offspring at various postnatal ages following MIA and to determine the effects of those cytokines on cortical neuron connectivity and function. Using the PolyI:C mouse model of MIA, Luminex multiplex cytokine arrays, immunocyto- and histochemistry, cell and slice culture, and whole-cell patch-clamp recording, we will address the following Aims. (1) Define the nature and time-course of changes in cytokines n four distinct brain regions of offspring following MIA. (2) Test combinations of altered cytokines on synaptic connectivity and function during early postnatal development. Results from this proposal will provide insight into the mechanism underlying the effects of MIA on brain development and function and will potentially identify novel targets for therapeutic intervention in ASD. PUBLIC HEALTH RELEVANCE: Although a wide range of environmental stimuli have been proposed to play a role in the pathogenesis of autism spectrum disorders, many of these stimuli have in common the ability to alter immune function. Since cytokines mediate the immune response, are present in the developing brain, and regulate cortical plasticity and connectivity, factors that alter cytokines during development may lead to changes in synaptic connectivity that contribute to ASD. The goals of this proposal are to define the full complement of cytokines that are changed in specific regions of the CNS of offspring at various postnatal ages following MIA and to determine the effects of those cytokines on connectivity and function in several cortical regions at the relevant postnatal ages.