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

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 Gmcsfrsuggesting 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 Principal component loadings for P1 and PC2 P60 P7 P0 P14 P30

Shedding light on the role of CX3CR1 in the pathogenesis of schizophrenia

“…It showed that the expression of the receptor gene was particularly up-regulated at the beginning of synaptogenesis (P7) and declined during the peak of this process and spine formation (P14). These age-specific changes in the Cx3cr1 transcript level implicate MIA-induced microglial dysfunctions that trigger alterations in cortical networks [178]. The evidence seems to support the reports on impaired anatomical and functional connectivity in the cerebral cortex of patients with schizophrenia [179][180][181].…”

“…were identified. A significant, although preliminary observation in the context of schizophrenia-associated abnormalities implementing the MIA model with Poly I:C was also provided by Estes et al [178] in their preprint article.…”

“…Furthermore, MIA did not influence PPI and led to a lasting decrease in CX3CR1 level in male offspring as the reduction was detected both in adolescence and adulthood [176]. Hui et al [177] showed data, where prenatal immune challenge with Poly I:C in mice resulted in partly sex-dependent behavioral schizophrenia-like disturbances (for instance increased repetitive behavior, anxiety, reduced sociability and deficits in PPI) but no disturbances in Cx3cl1 and Cx3cr1 gene expression in brains of offspring Cx3cr1 expression was particularly up-regulated at the beginning of synaptogenesis (P7) and declined during the peak of this process and spine formation (P14) [178] Poly I:C Female and male chimeric and transgenic mice CX3CR1-highly expressing monocytes Dendritic spine loss, impairments in learning-dependent dendritic spine formation and deficits in learning tasks [182] High-fat diet Female and male C57BL/6N ↓ Cx3cr1 (hippocampus) in adolescent male offspring ≡ Cx3cr1 (hippocampus) in adolescent female offspring Similar phenotypes in both sexes for IL-6-driven immune priming and microglial morphology Sex-dependent changes in transcriptomic and astrocytemicroglia interaction [183] ↑ (increased), ↓ (decreased), ≡…”

Increased RNA editing in maternal immune activation model of neurodevelopmental disease

“…Current evidence suggests that a combination of polygenic susceptibility and exposure to environmental risk during sensitive periods of brain development can impair neurodevelopment, and confer vulnerability to the development of MND [1][2][3][4][5] . Possible environmental risk factors for MND include intrauterine stressors, such as maternal bacterial and viral infections during pregnancy [6][7][8][9][10] .…”