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bioRxiv · 10.1101/490466

Maternal immune activation causes age-specific changes in cytokine receptor expression in offspring throughout development

Estes, M. L.·Elmer, B. M.·Carter, C. C.·McAllister, A. K.
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Abstract

Maternal infection is a shared environmental risk factor for a spectrum of neuropsychiatric disorders and animal models of maternal immune activation (MIA) exhibit a range of neuropathologies and behaviors with relevance to these disorders. In particular, MIA offspring show chronic, age- and region-dependent changes in brain cytokines, a feature seen in postmortem studies of individuals with neuropsychiatric disorders. These MIA-induced alterations in brain cytokines may index biological processes underlying progression to diagnosable neuropsychiatric disorders. However, cytokines signal through specific cytokine receptors to alter cellular processes and it is the levels of those receptors that are critical for signaling. Yet, it remains unknown whether MIA alters the expression of cytokine receptors in the brains of offspring throughout postnatal development. Here, we measured the expression of 23 cytokine receptors in the frontal cortex of MIA and control offspring from birth to adulthood using qPCR. MIA offspring show dynamic oscillating alterations in cytokine receptors during sensitive periods of neural growth and synaptogenesis. Of the many cytokine receptors altered in the FC of MIA offspring, five were significantly changed at multiple ages at levels over 2-fold relative to controls--Il1r1, Ifngr1, Il10ra, Cx3cr1 and Gmcsfr--suggesting persistent dysfunction within those pathways. In addition to facilitating immune responses, these cytokine receptors play critical roles in neuronal migration and maturation, synapse formation and elimination, and microglial function. Together with previously reported changes in cytokine levels in the brains of MIA offspring, our results show a decrease in cytokine signaling during the peak period of synaptogenesis and spine formation and an increase during periods of activity-dependent development and early adulthood. Overall, the oscillating, age-dependent cytokine receptor alterations in the FC of MIA offspring identified here may have diagnostic and therapeutic value for neuropsychiatric disorders with a neuro-immune etiology.\n\nResearch HighlightMaternal immune activation leads to long-lasting, oscillating changes in cytokine receptors in the frontal cortex of offspring throughout development.

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Estes, M. L., Elmer, B. M., Carter, C. C., McAllister, A. K.. 2018-12-08. Maternal immune activation causes age-specific changes in cytokine receptor expression in offspring throughout development. https://doi.org/10.1101/490466

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