Abstract
Chronic inflammation during pregnancy (e.g., preeclampsia, diabetes) is linked to increased risk for offspring neurodevelopmental disorders such as autism spectrum disorder (ASD). However, mediators of such exposures that could be targeted with maternal intervention are unclear, as few chronic gestational inflammation models have been tested. One potential mediator is interleukin-17 (IL-17), a pro-inflammatory cytokine implicated in neurodevelopmental disorders and gestational disease. To test chronic maternal IL-17 impacts on offspring, C57BL/6J dams were administered IL-17A continuously throughout pregnancy. Offspring were assessed for body weight; cortical volume, gene expression, and cellular composition; and adult behavior. IL-17A-condition offspring exhibited decreased somatic and cortical size at embryonic day 18 (E18) and as adults. mRNA sequencing of E18 cortex revealed 320 differentially expressed genes in males, but none in females. These were significantly enriched for ASD (Simons Foundation Autism Research Initiative), synaptic, and cell cycle genes. By adulthood, neocortical glial cell density and gene expression were decreased, while GABAergic synaptic gene expression was increased in males. Furthermore, IL-17A-condition male but not female offspring exhibited reduced anxiety-like behavior. Social approach deficits in males were negatively correlated with neocortical GABAergic synaptic gene expression. Chronic gestational IL-17A was sufficient to cause ASD-like phenotypes early and persistently in male offspring. This echoes the male bias, altered cortical development, and behavioral findings in ASD, suggesting that chronic maternal IL-17 contributes to offspring ASD pathogenesis. Furthermore, the trajectory from embryonically dysregulated synaptic and cell cycle genes to disrupted adult glia, inhibitory synapses, and behavior suggests a mechanism for chronic maternal IL-17 effects on offspring.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1008-1017 |
| Number of pages | 10 |
| Journal | Neuropsychopharmacology |
| Volume | 45 |
| Issue number | 6 |
| DOIs | |
| State | Published - May 1 2020 |
| Externally published | Yes |
Bibliographical note
Funding Information:This work was supported by the University of Iowa Center for Hypertension Research Pilot Grant Program; the Iowa Center for Research by Undergraduates; T32MH019113, the postdoctoral Iowa Neuroscience Specialty Program in Research Education (INSPIRE); and a University of Iowa DeLTA Center Research Grant. Some data were obtained at the Neural Circuits and Behavior Core at the Iowa Neuroscience Institute, supported in part by the Roy J. Carver Charitable Trust. The authors declare no conflict of interest.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to American College of Neuropsychopharmacology.
