Interleukin-6 produces behavioral deficits in pre-pubescent mice independent of neuroinflammation.

Maternal inflammation during pregnancy increases the offspring's risk of developing autism, ADHD, schizophrenia, and depression. Epidemiologic studies have demonstrated that maternal infections stimulate the production of interleukin-6 (IL-6), which can cross the placenta and fetal blood-brain barrier to alter brain development with functional and behavioral consequences. To model the effects of increased IL-6 between weeks 24-30 of human gestation, we injected male and female mice with 75 ng IL-6 twice daily, from P3 to P6. Our published studies have shown that this increases circulating IL-6 two-fold, alters post-pubescent ultrasonic vocalization patterns, reduces sociability, and increases self-grooming. However, most neurodevelopmental disorders in humans manifest in children as young as 2 years of age. Hence, a critical unexplored question is whether behavioral changes in immune activation models can be detected in pre-pubescent mice. Therefore, we evaluated early communication, sociability, and repetitive behaviors in pre-pubescent mice following the IL-6 treatment. A second open question is whether the cellular and behavioral changes are secondary to systemic or neuroinflammation. To address this question, we profiled 18 cytokines and chemokines in the circulation and CNS and evaluated eight immune cell types in P7 male and female brains following systemic IL-6 administration. We found an increase in ultrasonic vocalizations with simpler morphologies produced by the IL-6-injected male pups and a decrease in frequency in the female vocalizations upon removal from the nest at P7. The IL-6-treated male pups also socially interacted less when introduced to a novel mouse vs. controls as juveniles and spent almost twice as much time grooming themselves, a phenotype not present in the females. Tactile sensitivity was also increased, but only in the IL-6-treated female mice. The IL-6-treated mice had increased circulating IL-6 and IL-7 and reduced IL-13 at P7 that were no longer elevated at P14. There were no changes in brain levels of IL-6, IL-10, IL-13 or IL-17A mRNAs at P7. Altogether, these studies show that changes in the three core behavioral domains associated with several psychiatric disorders can be detected early in pre-pubescent mice following a transient developmental increase in IL-6. Yet, these behavioral alterations do not require neuroinflammation.