Complement contributes to hyperactive behavior in the 16p11.2 hemideletion mouse model

The complement system is a major component of the innate immune system and plays an important role in immune surveillance. Recent research has demonstrated that the complement system also plays pivotal roles in brain development, and dysregulation of complement is involved in neurodegenerative and neuropsychiatric disorders. However, the mechanisms by which the complement system contributes to neurodevelopmental disorders (NDDs) remain poorly understood. In this study, we find that the expression of a central regulator of the complement cascade, complement component 3 (C3), is upregulated in the striatum of mice modeling the 16p11.2 hemideletion (16p11.2 del). 16p11.2 del is among the most common copy number variations associated with NDDs including attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID). Pharmacological inhibition of the C3a receptor alleviates hyperactivity in 16p11.2 del mice, suggesting that elevated complement contributes to NDD-relevant behavioral changes. Due to the pro-inflammatory actions of the C3a receptor, we assess the cytokine environment in the striatum, a key neural substrate for locomotor behavior, and find that several inflammatory factors are upregulated in 16p11.2 del mice. Collectively, these results indicate that increased expression of the complement system, especially C3, mediates hyperactive behavior and is associated with a pro-inflammatory environment in the striatum of 16p11.2 del mice. Our results suggest that inhibition of an overactive complement system may be an effective strategy to ameliorate NDD symptoms resulting from 16p11.2 hemideletion including those associated with ADHD.