Article ID Journal Published Year Pages File Type
5557919 Progress in Neuro-Psychopharmacology and Biological Psychiatry 2017 8 Pages PDF
Abstract

•TLR4/NF-κB activation is associated with neuroimmune dysfunction.•A2AR expression regulates TLR4/NF-κB activation in BTBR mice.•A2AR agonist decreases TLR4/NF-κB expression in spleen and brain.•A2AR agonist treatment increases IL-27/IκBα activation.

Autism is a predominant neurodevelopmental disorder characterized by impaired communication, social deficits, and repetitive behaviors. Recent research has proposed that the impairment of innate immunity may play an important role in autism. Toll-like receptors (TLRs) are potential therapeutic targets against neuroinflammation. The BTBR T+ Itpr3tf/J (BTBR) mouse is a well-known model of autism, showing repetitive behaviors such as cognitive inflexibility and increased grooming as compared to C57BL/6 (B6) mice. Adenosine A2A receptor (A2AR) signaling is involved in inflammation, brain injury, and lymphocyte infiltration into the CNS, but the role of A2AR in autism remains unknown. We investigated the effect of A2AR antagonist SCH 5826 (SCH) and agonist CGS 21680 (CGS) on the expression levels of TLRs, IL-27, NF-κB p65, and IκBα in BTBR mice. Treatment of BTBR mice with SCH increased the percentage of splenic CD14+ TLR2+ cells, CD14+ TLR3+ cells, CD14+ TLR4+ cells, and decreased the percentage of CD14+ IL-27+ cells, as compared to the untreated BTBR mice. Our results reveal that BTBR mice treated with CGS had reversal of SCH-induced immunological responses. Moreover, mRNA and protein expression analyses confirmed increased expression of TLR2, TLR3, TLR4, and NF-κB p65 in brain tissue, and decreased IL-27 and IκBα expression following SCH treatment, as compared to the untreated-BTBR and CGS-treated BTBR mice. Together, these results suggest that the A2AR agonist corrects neuroimmune dysfunction observed in BTBR mice, and thus has the potential as a therapeutic approach in autism.

Related Topics
Life Sciences Neuroscience Biological Psychiatry
Authors
, , , , , ,