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.
Research Highlight Maternal immune activation leads to long-lasting, oscillating changes in cytokine receptors in the frontal cortex of offspring throughout development.
Acknowledgments
We wish to thank Dr. David C. Katz for consultation on statistics and editing the manuscript. This work was supported by a Stanley & Jacqueline Schilling Neuroscience Postdoctoral Research Fellowship (M.L.E.), Dennis Weatherstone Predoctoral Fellowships from Autism Speaks (#7825 M.L.E. and #6339 B.M.E.), the Letty and James Callinan and Cathy and Andrew Moley Fellowship from the ARCS Foundation (M.L.E.), a Dissertation Year Fellowship from the University of California Office of the President (M.L.E.), P50-MH106438-01 (C.S.C), and the University of California Davis Research Investments in Science and Engineering Program (A.K.M.).
Footnotes
Conflict of Interest: The authors declare no competing financial interests.