Early postnatal activation of A2ARs alleviates social deficits by attenuating the abnormal infiltration of peripheral neutrophils in the BTBR T + Itpr3 tf /J mouse model of autism

Abstract

Background Previous studies have mainly focused on the immediate effect of drugs on autism spectrum disorders (ASDs) and complex heterogeneous neurodevelopmental disorders that have been proven to be involved with the chronic inflammation of the central nervous system. Our prior work has explored the positive role of activation of adenosine 2A receptors (A2ARs) in protecting adult BTBR T+ Itpr3tf/J mice against autism-related behaviour from the early postnatal period. However, the exact mechanism underlying the protection of A2ARs has not been comprehensively investigated. Methods The persistent protection of early postnatal activation of A2ARs in adult BTBR mice was detected utilizing behaviour tests. Pathological variation in the peripheral blood of autism patients was analysed by transcriptomic analysis, including MROAST and protein–protein interaction (PPI) analysis. The clues were further explored and validated by real-time (RT) PCR, western blotting, immunohistochemistry and transcriptomic analysis in the mouse cortex. The blood brain barrier of mice was identified by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results Abnormal activation of myeloid cells, especially neutrophils, was detected in the peripheral blood of autism patients and the BTBR mouse cortex. The BBB permeability of BTBR mice was significantly increased, which may have facilitated the abnormal infiltration of neutrophils observed in the BTBR mouse cortex. Furthermore, the early postnatal activation of A2ARs effectively reverses the abnormal activation and invasion of neutrophils in the mouse cortex and might result in the significant moderation of autism-related behaviour in adult BTBR mice, followed by a decrease in chronic inflammation in the mouse cortex during the early postnatal period. Conclusions We found abnormal myeloid cells in autism patients and BTBR mice and increased infiltration of neutrophils in the mouse cortex. We concluded that the early activation of A2ARs could effectively decrease the autism-related behaviour of adult BTBR mice by reversing the abnormal activation of myeloid cells and the pathological invasion of neutrophils in the mouse cortex.

A Brief Overview of Neutrophils in Neurological Diseases

“…Past investigations found high levels of pro-inflammatory cytokines, including IL-6 and IL-17A, in ASD patients and autistic mice [114,115]. In ASD subjects, IL-17A produced by immune cells such as Th17 and monocytes/macrophages cells can activate neutrophils.…”